Tricyclic opioid modulators

ABSTRACT

The invention is directed to compounds of Formula (I) useful as delta and mu opioid receptor modulators. Pharmaceutical and veterinary compositions and methods of treating mild to severe pain and various diseases using compounds of the invention are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims priority to U.S. Provisional Patent ApplicationNo. 60/691,101, filed Jun. 16, 2005, which is hereby incorporated byreference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

BACKGROUND OF THE INVENTION

The term “opiate” has been used to designate pharmacologically activealkaloids derived from opium, e.g., morphine, codeine, and manysemi-synthetic congeners of morphine. After the isolation of peptidecompounds with morphine-like actions, the term opioid was introduced torefer generically to all drugs with morphine-like actions. Includedamong opioids are various peptides that exhibit morphine-like activity,such as endorphins, enkephalins and dynorphins. However, some sourcesuse the term “opiate” in a generic sense, and in such contexts, opiateand opioid are interchangeable. Additionally, the term opioid has beenused to refer to antagonists of morphine-like drugs as well as tocharacterize receptors or binding sites that combine with such agents.

Opioids are generally employed as analgesics, but they may have manyother pharmacological effects as well. Morphine and related opioidsproduce certain of their major effects on the central nervous anddigestive systems. The effects are diverse, including analgesia,drowsiness, mood changes, respiratory depression, dizziness, mentalclouding, dysphoria, pruritus, increased pressure in the biliary tract,decreased gastrointestinal motility, nausea, vomiting, and alterationsof the endocrine and autonomic nervous systems.

When therapeutic doses of morphine are given to patients with pain, theyreport that the pain is less intense, less discomforting, or entirelygone. In addition to experiencing relief of distress, some patientsexperience euphoria. However, when morphine in a selected pain-relievingdose is given to a pain-free individual, the experience is not alwayspleasant; nausea is common, and vomiting may also occur. Drowsiness,inability to concentrate, difficulty in mentation, apathy, lessenedphysical activity, reduced visual acuity, and lethargy may ensue.

Two distinct classes of opioid molecules can bind opioid receptors: theopioid peptides (e.g., the enkephalins, dynorphins, and endorphins) andthe alkaloid opiates (e.g., morphine, etorphine, diprenorphine andnaloxone). Subsequent to the initial demonstration of opiate bindingsites (Pert, C. B. and Snyder, S. H., Science (1973) 179:1011-1014), thedifferential pharmacological and physiological effects of both opioidpeptide analogues and alkaloid opiates served to delineate multipleopioid receptors. Accordingly, three molecularly and pharmacologicallydistinct opioid receptor types have been described: delta, kappa and mu.Furthermore, each type is believed to have sub-types (Wollemann, M., JNeurochem (1990) 54:1095-1101; Lord, J. A., et al., Nature (1977)267:495-499).

All three of these opioid receptor types appear to share the samefunctional mechanisms at a cellular level. For example, the opioidreceptors cause inhibition of adenylate cyclase, and inhibition ofneurotransmitter release via both potassium channel activation andinhibition of Ca²⁺ channels (Evans, C. J., In: Biological Basis ofSubstance Abuse, S. G. Korenman & J. D. Barchas, eds., Oxford UniversityPress (in press); North, A. R., et al., Proc Natl Acad Sci USA (1990)87:7025-29; Gross, R. A., et al., Proc Natl Acad Sci USA (1990)87:7025-29; Sharma, S. K., et al., Proc Natl Acad Sci USA (1975)72:3092-96). Although the functional mechanisms are the same, thebehavioral manifestations of receptor-selective drugs differ greatly(Gilbert, P. E. & Martin, W. R., J Pharmacol Exp Ther (1976) 198:66-82).Such differences may be attributable in part to the anatomical locationof the different receptors.

Delta receptors have a more discrete distribution within the mammalianCNS than either mu or kappa receptors, with high concentrations in theamygdaloid complex, striatum, substantia nigra, olfactory bulb,olfactory tubercles, hippocampal formation, and the cerebral cortex(Mansour, A., et al., Trends in Neurosci (1988) 11:308-14). The ratcerebellum is remarkably devoid of opioid receptors including deltaopioid receptors.

D. Delorme, E. Roberts and Z. Wei, World Patent WO/28275 (1998)discloses diaryl methylidenylpiperidines that are opioid analgesics, butdoes not disclose or suggest the compounds of the present invention.

C. Kaiser, and others (J. Med. Chem. 1974, Volume 17, pages 57-61)disclose some piperidylidene derivatives of thioxanthenes, xanthenes,dibenoxepins and acridans that are neuroleptic agents. These authors,however, do not disclose or suggest either the structure or the activityof the compounds of the present invention.

British Patent GB 1128734 (1966) discloses derivatives of6,11-dihydrodibenzo[b,e]oxepine that are anticholinergic,anti-convulsive, muscle-relaxing, sedating, diuretic, and/or vasoactiveagents. These, agents, however, differ significantly from the compoundsof the present invention both structurally and pharmacologically.

J. Neumeyer, M. Wentland, and others have disclosed morphine andcyclazocine derivatives wherein their 8-hydroxy group has been replacedby various amino and substituted amino groups (Neumeyer, John L. et al.J Med. Chem. 2004, 47 165-174; Wentland, Mark P. et al. Bioorg. Med.Chem. Lett. 2003, 13,1911-1914; Wentland, Mark P. et al. J. Med. Chem.2000, 43,3558-3565; and Wentland, Mark P. et al. J. Med. Chem. 2003, 46,838-849).

PCT patent WO 02/36573 discloses8-substituted-2,6-methano-3-benzazocines that are useful as analgesics,anti-diarrheal agents, anticonvulsants, antitussives, and anti-addictionmedications.

U.S. Pat. No. 4,001,419 discloses 1′-substitutedxanthene-9-spiro-4′-piperidine derivatives which possess analgesicactivity, but does not disclose or suggest compounds of the presentinvention.

There is a continuing need for new opioid receptor modulators asanalgesics. There is a further need for delta and mu opioid receptoragonists as analgesics having reduced side effects. There is a furtherneed for mu opioid receptor agonists as analgesics having reduced sideeffects for the treatment of pain, immune function, esophageal reflux,and cough. There is also a need for delta opioid receptor agonists asanalgesic agents, agents for the treatment of respiratory diseases,cardiovascular agents, agents for treating urological dysfunction, andagents for the treatment of neurological and psychiatric conditions.There is further need for dual delta opioid receptor/mu opioid receptoragonists.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of Formula (I):

wherein:

-   -   R₁is hydroxy; mercapto; aminocarbonyl; C₁₋₄alkanylaminocarbonyl;        di(C₁₋₄alkanyl)aminocarbonyl;        di(C₁₋₄alkanyl)amino-C₁₋₄alkyl-aminocarbonyl;        phenyl-aminocarbonyl; phenyl(C₁₋₄)alkanylaminocarbonyl;        C₁₋₄alkanyloxycarbonyl; aminothiocarbonyl; amidino;        hydroxyamidino; phenylcarbonyl; —C(═NOH)phenyl; amino;        C₁₋₄alkanylamino; di(C₁₋₄alkanyl)amino;    -   aminomethyl; hydroxymethyl; C₁₋₄alkanylsulfonylamino;        C₆₋₁₀arylamino wherein C₆₋₁₀aryl is optionally substituted with        one to three substitutents independently selected from the group        consisting of C₁₋₆alkanyl, C₁₋₆alkoxy, halogen, and hydroxy;        dihydroimidazolyl; formylamino; thioformylamino; or        pyridinylamino; or, optionally, R₁ is —S—C(NH₂)═N— to form a        fused moiety in which the second point of attachment is an        adjacent non-bridging carbon atom;

-   R₂ is a substituent selected from the group consisting of hydrogen,    C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,    C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,    C₁₋₈alkanytoxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,    hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,    halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,    phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkenyl,    phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl and    heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected from the    group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,    pyridinyl, thienyl, indazolyl, indolyl, indolinyl, isoindolinyl,    isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,    pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,    isoquinolinyl, benzothiophenyl, tetrazolyl, and thiazolyl; wherein    phenyl, naphthyl and heteroaryl are optionally substituted with    phenyl, and one to three substituents independently selected from    the group consisting of C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy,    amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,    C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio,    C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano, fluoro(C₁₋₆)alkanyl,    thioureido, and fluoro(C₁₋₆)alkanyloxy; alternatively, when phenyl    and heteroaryl are optionally substituted with alkanyl or alkanyloxy    substituents attached to adjacent carbon atoms, the two substituents    can together form a fused cyclic alkanyl or cycloheteroalkanyl    selected from the group consisting of —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—,    —(CH₂)₂₋₄O—, and —O(CH₂)₁₋₃O—;

-   A is absent or —(CH₂)₂₋₃—;

-   Y is O or S;

-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

Finally, the present invention is directed to veterinary andpharmaceutical compositions containing compounds of Formula (I) whereinthe compositions are used to treat mild to severe pain in warm-bloodedanimals

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following underlined terms are intended to have thefollowing meanings:

“C_(a-b)” (where a and b are integers) refers to a radical containingfrom a to b carbon atoms inclusive. For example, C₁₋₃ denotes a radicalcontaining 1, 2 or 3 carbon atoms

“Alkyl:” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Wherespecific levels of saturation are intended, the nomenclature “alkanyl”,“alkenyl” and/or “alkynyl” is used, as defined below. In preferredembodiments, the alkyl groups are (C₁-C₆) alkyl, with (C₁-C₃) beingparticularly preferred.

“Alkanyl:” refers to a saturated branched, straight-chain or cyclicmonovalent hydrocarbon radical derived by the removal of one hydrogenatom from a single carbon atom of a parent alkane. Typical alkanylgroups include, but are not limited to, methanyl; ethanyl; propanylssuch as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.; butyanyls suchas butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,cyclobutan-1-yl, etc.; and the like. In preferred embodiments, thealkanyl groups are (C₁₋₈) alkanyl, with (C₁₋₃) being particularlypreferred.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicmonovalent hydrocarbon radical having at least one carbon-carbon doublebond derived by the removal of one hydrogen atom from a single carbonatom of a parent alkene. The radical may be in either the cis or transconformation about the double bond(s). Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl” refers to an unsaturated branched, straight-chain or cyclicmonovalent hydrocarbon radical having at least one carbon-carbon triplebond derived by the removal of one hydrogen atom from a single carbonatom of a parent alkyne. Typical alkynyl groups include, but are notlimited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl,etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl,etc.; and the like.

“Heteroalkyl” and Heteroalkanyl” refer to alkyl or alkanyl radicals,respectively, in which one or more carbon atoms (and any necessaryassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatoms (including any necessary hydrogen or other atoms).Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Preferred heteroatoms are O, N and S.Thus, heteroalkanyl radicals can contain one or more of the same ordifferent heteroatomic groups, including, by way of example and notlimitation, epoxy (—O—), epidioxy (—O—O—), thioether (—S—), epidithio(—SS—), epoxythio (—O—S—), epoxyimino (—O—NR′—), imino (—NR′—), biimino(—NR′—NR′—), azino (═N—N═), azo (—N═N—), azoxy (—N—O—N—), azimino(—NR′—N═N—), phosphano (—PH—), λ⁴-sulfano (—SH₂—), sulfonyl (—S(O)₂—),and the like, where each R′ is independently hydrogen or (C₁-C₆) alkyl.

“Aryl:” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, pentacene, pentalene, pentaphene, perylene, phenalene,phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene,triphenylene, trinaphthalene, and the like. In preferred embodiments,the aryl group is (C₅₋₂₀) aryl, with (C₅₋₁₀) being particularlypreferred. Particularly preferred aryl groups are phenyl and naphthylgroups.

“Arylalkyl:” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal carbonatom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylakenyl and/or arylalkynyl is used. [In preferredembodiments, the arylalkyl group is (C₆₋₂₆) arylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁₋₆) andthe aryl moiety is (C₅₋₂₀). In particularly preferred embodiments thearylalkyl group is (C₆₋₁₃), e.g., the alkanyl, alkenyl or alkynyl moietyof the arylalkyl group is (C₁₋₃) and the aryl moiety is (C₅₋₁₀). Evenmore preferred arylalkyl groups are phenylalkanyls.

“Alkanyloxy:” refers to a saturated branched, straight-chain or cyclicmonovalent hydrocarbon alcohol radical derived by the removal of thehydrogen atom from the hydroxide oxygen of the alcohol. Typicalalkanyloxy groups include, but are not limited to, methanyloxy;ethanyloxy; propanyloxy groups such as propan-1-yloxy (CH₃CH₂CH₂O—),propan-2-yloxy ((CH₃)₂CHO—), cyclopropan-1-yloxy, etc.; butanyloxygroups such as butan-1-yloxy, butan-2-yloxy, 2-methyl-propan-1-yloxy,2-methyl-propan-2-yloxy, cyclobutan-1-yloxy, etc.; and the like. Inpreferred embodiments, the alkanyloxy groups are (C₁₋₈) alkanyloxygroups, with (C₁₋₃) being particularly preferred.

“Heteroaryl:” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, radicals derived from carbazole, imidazole, indazole,indole, indoline, indolizine, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine,pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In preferred embodiments, the heteroaryl group is a 5-20 memberedheteroaryl, with 5-10 membered heteroaryl being particularly preferred.

“Cycloheteroalkyl:” refers to a saturated or unsaturated monocyclic orbicyclic alkyl radical in which one carbon atom is replaced with N, O orS. In certain specified embodiments the cycloheteroalkyl may contain upto four heteroatoms independently selected from N, O or S. Typicalcycloheteroalkyl moieties include, but are not limited to, radicalsderived from imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidine, quinuclidine, and the like. In preferredembodiments, the cycloheteroalkyl is a 3-6 membered cycloheteroalkyl.

“Cycloheteroalkanyl:” refers to a saturated monocyclic or bicyclicalkanyl radical in which one carbon atom is replaced with N, O or S. Incertain specified embodiments the cycloheteroalkanyl may contain up tofour heteroatoms independently selected from N, O or S. Typicalcycloheteroalkanyl moieties include, but are not limited to, radicalsderived from imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidine, quinuclidine, and the like. In preferredembodiments, the cycloheteroalkanyl is a 3-6 memberedcycloheteroalkanyl.

“Cycloheteroalkenyl:” refers to a saturated monocyclic or bicyclicalkenyl radical in which one carbon atom is replaced with N, O or S. Incertain specified embodiments the cycloheteroalkenyl may contain up tofour heteroatoms independently selected from N, O or S. Typicalcycloheteroalkenyl moieties include, but are not limited to, radicalsderived from imidazoline, pyrazoline, pyrroline, indoline, pyran, andthe like. In preferred embodiments, the cycloheteroalkanyl is a 3-6membered cycloheteroalkanyl.

“Substituted:” refers to a radical in which one or more hydrogen atomsare each independently replaced with the same or differentsubstituent(s). Typical substituents include, but are not limited to,—X, —R, —O⁻, ═O, —OR, —O—OR, —SR, —S⁻, ═S, —NRR, ═NR, —CX₃, —CN, —OCN,—SCN, —NCO, —NCS, —NO, —NO₂, ═N₂, —N₃, —NHOH, —S(O)₂O⁻, —S(O)₂OH,—S(O)₂R, —P(O)(O⁻)₂, —P(O)(OH)₂, —C(O)R, —C(O)X, —C(S)R, —C(S)X,—C(O)OR, —C(O)O⁻, —C(S)OR, —O(O)SR, —C(S)SR, —O(O)NRR, —C(S)NRR and—C(NR)NRR, where each X is independently a halogen (preferably —F, —Clor —Br) and each R is independently —H, alkyl, alkanyl, alkenyl,alkynyl, alkylidene, alkylidyne, aryl, arylalkyl, arylheteroalkyl,heteroaryl, heteroarylalkyl or heteroaryl-heteroalkyl, as definedherein. Preferred substituents include hydroxy, halogen, C₁₋₈alkyl,C₁₋₈alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl,C₁₋₈alkylthio, C₃₋₈cycloalkyl, C₃₋₈cycloalkanyloxy, nitro, amino,C₁₋₈alkylamino, C₁₋₈dialkylamino, C₃₋₈cycloalkylamino, cyano, carboxy,C₁₋₇alkanyloxycarbonyl, C₁₋₇alkylcarbonyloxy, formyl, carbamoyl, phenyl,aroyl, carbamoyl, amidino, (C₁₋₈alkylamino)carbonyl, (arylamino)carbonyland aryl(C₁₋₈alkyl)carbonyl.

With reference to substituents, the term “independently” means that whenmore than one of such substituent is possible, such substituents may bethe same or different from each other.

Throughout this disclosure, the terminal portion of the designated sidechain is described first, followed by the adjacent functionality towardthe point of attachment. Thus, for example, a

-   “phenylC₁₋₆alkanylaminocarbonylC₁₋₆alkanyl” substituent refers to a    group of the formula

An embodiment of the present invention is directed to a compound ofFormula (I) wherein the structure is numbered as defined herein.

The present invention is directed to analgesic uses of compositionscomprising a compound of Formula (I):

wherein:

-   R₁ is hydroxy; mercapto; aminocarbonyl; C₁₋₄alkanylaminocarbonyl;    di(C₁₋₄alkanyl)aminocarbonyl; (phenylmethyl)aminocarbonyl;    (4-methoxy-phenylmethyl)aminocarbonyl; C₁₋₄alkanyloxycarbonyl;    aminothiocarbonyl; amidino; hydroxyamidino; phenylcarbonyl;    —C(═NOH)phenyl; amino; C₁₋₄alkanylamino; di(C₁₋₄alkanyl)amino;    aminomethyl; hydroxymethyl; methanesulfonylamino; C₆₋₁₀arylamino    wherein C₆₋₁₀aryl is optionally substituted with one to three    substitutents independently selected from the group consisting of    C₁₋₆alkanyl, C₁₋₆alkoxy, halogen, and hydroxy; dihydroimidazolyl;    formylamino; thioformylamino; or pyridinylamino; or, optionally, R₁    is —S—C(NH₂)═N— to form a fused moiety in which the second point of    attachment is an adjacent non-bridging carbon atom;-   R₂ is a substituent selected from the group consisting of hydrogen,    C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,    C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,    C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,    hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,    halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,    phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkenyl,    phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl and    heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected from the    group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,    pyridinyl, thienyl, indazolyl, indolyl, indolinyl, isoindolinyl,    isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,    pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,    isoquinolinyl, tetrazolyl, thiazolyl; wherein phenyl, naphthyl and    heteroaryl are optionally substituted with phenyl, and one to three    substituents independently selected from the group consisting of    C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino,    di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy,    C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl,    halogen, hydroxy, cyano, fluoro(C₁₋₆)alkanyl, thioureido, and    fluoro(C₁₋₆)alkanyloxy; alternatively, when phenyl and heteroaryl    are optionally substituted with alkanyl or alkanyloxy substituents    attached to adjacent carbon atoms, the two substituents can together    form a fused cyclic alkanyl or cycloheteroalkanyl selected from the    group consisting of —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—, —(CH₂)₂₋₄O—, and    —O(CH₂)₁₋₃O—;-   A is absent or —(CH₂)₂₋₃—;-   Y is O or S;-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to anti-pyreticuses of compositions comprising a compound of Formula (I):

wherein:

-   R₁ is hydroxy; mercapto; aminocarbonyl; C₁₋₄alkanylaminocarbonyl;    di(C₁₋₄alkanyl)aminocarbonyl; (phenylmethyl)aminocarbonyl;    (4-methoxy-phenylmethyl)aminocarbonyl; C₁₋₄alkanyloxycarbonyl;    aminothiocarbonyl; amidino; hydroxyamidino; phenylcarbonyl;    —C(═NOH)phenyl; amino; C₁₋₄alkanylamino; di(C₁₋₄alkanyl)amino;    aminomethyl; hydroxymethyl; methanesulfonylamino; C₆₋₁₀arylamino    wherein C₆₋₁₀aryl is optionally substituted with one to three    substitutents independently selected from the group consisting of    C₁₋₆alkanyl, C₁₋₆alkoxy, halogen, and hydroxy; dihydroimidazolyl;    formylamino; thioformylamino; or pyridinylamino; or, optionally, R₁    is —S—C(NH₂)═N— to form a fused moiety in which the second point of    attachment is an adjacent non-bridging carbon atom;-   R₂ is a substituent selected from the group consisting of hydrogen,    C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,    C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,    C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,    hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,    halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,    phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkenyl,    phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl and    heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected from the    group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,    pyridinyl, thienyl, indazolyl, indolyl, indolinyl, isoindolinyl,    isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,    pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,    isoquinolinyl, tetrazolyl, thiazolyl; wherein phenyl, naphthyl and    heteroaryl are optionally substituted with phenyl, and one to three    substituents independently selected from the group consisting of    C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy, amino, C₁₋₆alkanylamino,    di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl, C₁₋₆alkanylcarbonyloxy,    C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio, C₁₋₆alkanylsulfonyl,    halogen, hydroxy, cyano, fluoro(C₁₋₆)alkanyl, thioureido, and    fluoro(C₁₋₆)alkanyloxy; alternatively, when phenyl and heteroaryl    are optionally substituted with alkanyl or alkanyloxy substituents    attached to adjacent carbon atoms, the two substituents can together    form a fused cyclic alkanyl or cycloheteroalkanyl selected from the    group consisting of —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—, —(CH₂)₂₋₄O—, and    —O(CH₂)₁₋₃O—;-   A is absent or —(CH₂)₂₋₃—;-   Y is O or S;-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

Embodiments of the present invention include compounds of Formula (I)wherein:

-   -   a) R₁ is hydroxy, aminocarbonyl, aminothiocarbonyl;        hydroxyamidino, or formylamino;    -   b) R₁ is hydroxy or aminocarbonyl;    -   c) R₁ is hydroxy;    -   d) R₂ is selected from the group consisting of hydrogen,        C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,        C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,        hydroxyC₁₋₈alkanyl, thioformyl, phenylimino(C₁₋₈)alkanyl,        phenyl(C₁₋₈)alkanyl, and heteroaryl(C₁₋₈)alkanyl wherein        heteroaryl is selected from the group consisting of        benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl,        indolyl, indolinyl, isoquinolinyl, pyrazinyl, pyrazolyl,        pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl,        tetrazolyl; wherein phenyl and heteroaryl are optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₆alkanyloxy and        hydroxy; or optionally, when phenyl and heteroaryl are        optionally substituted with two substituents attached to        adjacent carbon atoms, the two substituents together form        —O(CH₂)₁₋₃O—;    -   e) R₂ is selected from the group consisting of hydrogen, methyl,        allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl,        methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and        heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected from        the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,        pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl,        isoquinolinyl, tetrazolyl; wherein the phenyl in any        phenyl-containing substituent is optionally substituted with a        hydroxyl group;    -   f) R₂ is hydrogen, methyl, allyl, or heteroarylmethyl wherein        heteroaryl is selected from the group consisting of        benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, and thienyl;    -   g) R₂ is hydrogen;    -   h) A is absent or —(CH₂)₂—;    -   i) A is —(CH₂)₂—;    -   j) Y is O;        and combinations of a) through j) above.

One embodiment of the present invention is a compound of Formula (I)wherein:

-   R₁ is hydroxy, aminocarbonyl, aminothiocarbonyl; hydroxyamidino, or    formylamino;-   R₂ is selected from the group consisting of hydrogen, C₁₋₈alkanyl,    C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkanyloxy(C₁₋₈)alkanyl,    C₁₋₈alkanylthio(C₁₋₈)alkanyl, hydroxyC₁₋₈alkanyl, thioformyl,    phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl, and    heteroaryl(C₁₋₈)alkanyl wherein heteroaryl is selected from the    group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,    pyridinyl, thienyl, indolyl, indolinyl, isoquinolinyl, pyrazinyl,    pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,    isoquinolinyl, tetrazolyl; wherein phenyl and heteroaryl are    optionally substituted with one to three substituents independently    selected from the group consisting of C₁₋₆alkanyloxy and hydroxy; or    optionally, when phenyl and heteroaryl are optionally substituted    with two substituents attached to adjacent carbon atoms, the two    substituents together form —O(CH₂)₁₋₃O—;-   A is absent or —(CH₂)₂—;-   Y is O;-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of Formula (I)wherein:

-   R₁ is hydroxy or aminocarbonyl;-   R₂ is selected from the group consisting of hydrogen, methyl, allyl,    2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl,    methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and    heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected from the    group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,    pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl,    isoquinolinyl, tetrazolyl; wherein the phenyl in any    phenyl-containing substituent is optionally substituted with a    hydroxyl group;-   A is —(CH₂)₂—;-   Y is O;-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of Formula (I)wherein:

-   R₁ is hydroxy;-   R₂ is hydrogen, methyl, allyl, or heteroarylmethyl wherein    heteroaryl is selected from the group consisting of    benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, and thienyl;-   A is —(CH₂)₂—;-   Y is O;-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of Formula (I)wherein:

-   R₁ is hydroxy;-   R₂ is hydrogen;-   A is —(CH₂)₂—;-   Y is O;-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

The present invention is also directed to analgesic uses of compositionscomprising a compound of Formula (I):

wherein:

-   R₁ is hydroxy; mercapto; aminocarbonyl; C₁₋₄alkanylaminocarbonyl;    di(C₁₋₄alkanyl)aminocarbonyl;    di(C₁₋₄alkanyl)amino-C₁₋₄alkyl-aminocarbonyl; phenyl-aminocarbonyl;    phenyl(C₁₋₄)alkanylaminocarbonyl; C₁₋₄alkanyloxycarbonyl;    aminothiocarbonyl; amidino; hydroxyamidino; phenylcarbonyl;    —C(═NOH)phenyl; amino; C₁₋₄alkanylamino; di(C₁₋₄alkanyl)amino;    aminomethyl; hydroxymethyl; C₁₋₄alkanylsulfonylamino; C₆₋₁₀arylamino    wherein C₆₋₁₀aryl is optionally substituted with one to three    substitutents independently selected from the group consisting of    C₁₋₆alkanyl, C₁₋₆alkoxy, halogen, and hydroxy; dihydroimidazolyl;    formylamino; thioformylamino; or pyridinylamino; or, optionally, R₁    is —S—C(NH₂)═N— to form a fused moiety in which the second point of    attachment is an adjacent non-bridging carbon atom;-   R₂ is a substituent selected from the group consisting of hydrogen,    C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,    C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,    C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,    hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,    halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,    phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkenyl,    phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl and    heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected from the    group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,    pyridinyl, thienyl, indazolyl, indolyl, indolinyl, isoindolinyl,    isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,    pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,    isoquinolinyl, benzothiophenyl, tetrazolyl, and thiazolyl; wherein    phenyl, naphthyl and heteroaryl are optionally substituted with    phenyl, and one to three substituents independently selected from    the group consisting of C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy,    amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,    C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio,    C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano, fluoro(C₁₋₆)alkanyl,    thioureido, and fluoro(C₁₋₆)alkanyloxy; alternatively, when phenyl    and heteroaryl are optionally substituted with alkanyl or alkanyloxy    substituents attached to adjacent carbon atoms, the two substituents    can together form a fused cyclic alkanyl or cycloheteroalkanyl    selected from the group consisting of —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—,    —(CH₂)₂₋₄O—, and —O(CH₂)₁₋₃O—;-   A is absent or —(CH₂)₂₋₃—;-   Y is O or S;-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to anti-pyreticuses of compositions comprising a compound of Formula (I):

wherein:

-   R₁ is hydroxy; mercapto; aminocarbonyl; C₁₋₄alkanylaminocarbonyl;    di(C₁₋₄alkanyl)aminocarbonyl;    di(C₁₋₄alkanyl)amino-C₁₋₄alkyl-aminocarbonyl; phenyl-aminocarbonyl;    phenyl(C₁₋₄)alkanylaminocarbonyl; C₁₋₄alkanyloxycarbonyl;    aminothiocarbonyl; amidino; hydroxyamidino; phenylcarbonyl;    —C(═NOH)phenyl; amino; C₁₋₄alkanylamino; di(C₁₋₄alkanyl)amino;    aminomethyl; hydroxymethyl; C₁₋₄alkanylsulfonylamino; C₆₋₁₀arylamino    wherein C₆₋₁₀aryl is optionally substituted with one to three    substitutents independently selected from the group consisting of    C₁₋₆alkanyl, C₁₋₆alkoxy, halogen, and hydroxy; dihydroimidazolyl;    formylamino; thioformylamino; or pyridinylamino; or, optionally, R₁    is —S—C(NH₂)═N— to form a fused moiety in which the second point of    attachment is an adjacent non-bridging carbon atom;-   R₂ is a substituent selected from the group consisting of hydrogen,    C₁₋₈alkanyl, halo₁₋₃(C₁₋₈)alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,    C₃₋₈cycloalkanyl, cycloalkanyl(C₁₋₈)alkanyl,    C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,    hydroxyC₁₋₈alkanyl, C₁₋₈alkanyloxycarbonyl,    halo₁₋₃(C₁₋₈)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl,    phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkenyl,    phenyl(C₁₋₈)alkynyl, naphthyl(C₁₋₈)alkanyl and    heteroaryl(C₁₋₈)alkanyl wherein the heteroaryl is selected from the    group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,    pyridinyl, thienyl, indazolyl, indolyl, indolinyl, isoindolinyl,    isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,    pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,    isoquinolinyl, benzothiophenyl, tetrazolyl, and thiazolyl; wherein    phenyl, naphthyl and heteroaryl are optionally substituted with    phenyl, and one to three substituents independently selected from    the group consisting of C₁₋₆alkanyl, C₂₋₆alkenyl, C₁₋₆alkanyloxy,    amino, C₁₋₆alkanylamino, di(C₁₋₆alkanyl)amino, C₁₋₆alkanylcarbonyl,    C₁₋₆alkanylcarbonyloxy, C₁₋₆alkanylcarbonylamino, C₁₋₆alkanylthio,    C₁₋₆alkanylsulfonyl, halogen, hydroxy, cyano, fluoro(C₁₋₆)alkanyl,    thioureido, and fluoro(C₁₋₆)alkanyloxy; alternatively, when phenyl    and heteroaryl are optionally substituted with alkanyl or alkanyloxy    substituents attached to adjacent carbon atoms, the two substituents    can together form a fused cyclic alkanyl or cycloheteroalkanyl    selected from the group consisting of —(CH₂)₃₋₅—, —O(CH₂)₂₋₄—,    —(CH₂)₂₋₄O—, and —O(CH₂)₁₋₃O—;-   A is absent or —(CH₂)₂₋₃—;-   Y is O or S;-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

Embodiments of the present invention include compounds of Formula (I)wherein:

-   a) R₁ is hydroxy, aminocarbonyl, hydroxyamidino, formylamino;    C₁₋₄alkanylaminocarbonyl; phenyl-aminocarbonyl;    phenyl(C₁₋₄)alkanylaminocarbonyl; C₆₋₁₀arylamino wherein C₆₋₁₀aryl    is optionally substituted with one to two substitutents    independently selected from the group consisting of C₁₋₄alkanyl,    C₁₋₄alkoxy, halogen, and hydroxy; or pyridinylamino;-   b) R₁ is hydroxy, aminocarbonyl, hydroxyamidino, formylamino;    C₁₋₄alkanylaminocarbonyl; phenyl-aminocarbonyl;    phenyl(C₁₋₄)alkanylaminocarbonyl; or pyridinylamino;-   c) R₁ is hydroxy, aminocarbonyl, formylamino; phenyl-aminocarbonyl;    or phenyl(C₁₋₄)alkanylaminocarbonyl;-   d) R₁ is hydroxy, aminocarbonyl, formylamino; phenyl-aminocarbonyl;    or phenylmethylaminocarbonyl;-   e) R₂ is selected from the group consisting of hydrogen,    C₁₋₈alkanyl, C₂₋₈alkenyl, C₂₋₈alkynyl,    C₃₋₈-cycloalkanyl(C₁₋₈)alkanyl, C₁₋₈alkanyloxy(C₁₋₈)alkanyl,    C₁₋₈alkanylthio(C₁₋₈)alkanyl, hydroxyC₁₋₈alkanyl, thioformyl,    phenylimino(C₁₋₈)alkanyl, phenyl(C₁₋₈)alkanyl, and    heteroaryl(C₁₋₈)alkanyl wherein heteroaryl is selected from the    group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,    pyridinyl, thienyl, indolyl, indolinyl, isoquinolinyl, pyrazinyl,    pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,    isoquinolinyl, benzothiophenyl, tetrazolyl; wherein phenyl and    heteroaryl are optionally substituted with one to three substituents    independently selected from the group consisting of C₁₋₆alkanyloxy    and hydroxy; or optionally, when phenyl and heteroaryl are    optionally substituted with two substituents attached to adjacent    carbon atoms, the two substituents together form —O(CH₂)₁₋₃O—;-   f) R₂ is selected from the group consisting of hydrogen, methyl,    allyl, 2-methyl-allyl, 3-methyl-but-2-enyl, propynyl, hydroxyethyl,    C₃₋₅cycloalkanylmethyl, methylthioethyl, methoxyethyl, thioformyl,    phenyliminomethyl, phenethyl, and heteroaryl(C₁₋₂)alkanyl wherein    the heteroaryl is selected from the group consisting of    benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl,    pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, benzothiophenyl,    tetrazolyl; wherein the phenyl in any phenyl-containing substituent    and the pyridinyl substituent are optionally substituted with one    hydroxyl group;-   g) R₂ is hydrogen, methyl, allyl, 3-methyl-but-2-enyl,    cyclopropylmethyl, phenylmethyl, or heteroarylmethyl wherein    heteroaryl is selected from the group consisting of    benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, and thienyl;-   h) R₂ is hydrogen, methyl, 3-methyl-but-2-enyl, cyclopropylmethyl,    phenylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl,    pyridin-4-ylmethyl, 2-hydroxy-pyridin-4-ylmethyl,    imidazol-2-ylmethyl, thien-2-ylmethyl, or furan-3-ylmethyl;-   i) A is absent or —(CH₂)₂—;-   j) A is —(CH₂)₂—;-   k) Y is O;    and combinations of a) through k) above.

One embodiment of the present invention is a compound of Formula (I)wherein:

-   R₁ is hydroxy, aminocarbonyl, hydroxyamidino, formylamino;    C₁₋₄alkanylaminocarbonyl; phenyl-aminocarbonyl;    phenyl(C₁₋₄)alkanylaminocarbonyl; C₆₋₁₀arylamino wherein C₆₋₁₀ aryl    is optionally substituted with one to two substitutents    independently selected from the group consisting of C₁₋₄alkanyl,    C₁₋₄alkoxy, halogen, and hydroxy; or pyridinylamino;-   R₂ is selected from the group consisting of hydrogen, C₁₋₈alkanyl,    C₂₋₈alkenyl, C₂₋₈alkynyl, C₃₋₈cycloalkanyl(C₁₋₈)alkanyl,    C₁₋₈alkanyloxy(C₁₋₈)alkanyl, C₁₋₈alkanylthio(C₁₋₈)alkanyl,    hydroxyC₁₋₈alkanyl, thioformyl, phenylimino(C₁₋₈)alkanyl,    phenyl(C₁₋₈)alkanyl, and heteroaryl(C₁₋₈)alkanyl wherein heteroaryl    is selected from the group consisting of benzo[1,3]dioxolyl,    imidazolyl, furanyl, pyridinyl, thienyl, indolyl, indolinyl,    isoquinolinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,    pyrrolyl, quinolinyl, isoquinolinyl, benzothiophenyl, tetrazolyl;    wherein phenyl and heteroaryl are optionally substituted with one to    three substituents independently selected from the group consisting    of C₁₋₆alkanyloxy and hydroxy; or optionally, when phenyl and    heteroaryl are optionally substituted with two substituents attached    to adjacent carbon atoms, the two substituents together form    —O(CH₂)₁₋₃O—;-   A is absent or —(CH₂)₂—;-   Y is O;-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of Formula (I)wherein:

-   R₁ is hydroxy, aminocarbonyl, formylamino; phenyl-aminocarbonyl; or    pyridinylamino;-   R₂ is selected from the group consisting of hydrogen, methyl, allyl,    2-methyl-allyl, 3-methyl-but-2-enyl, propynyl, hydroxyethyl,    C₃₋₅cycloalkanylmethyl, methylthioethyl, methoxyethyl, thioformyl,    phenyliminomethyl, phenethyl, and heteroaryl(C₁₋₂)alkanyl wherein    the heteroaryl is selected from the group consisting of    benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl,    pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, benzothiophenyl,    tetrazolyl; wherein the phenyl in any phenyl-containing substituent    and the pyridinyl substituent are optionally substituted with one    hydroxyl group;-   A is —(CH₂)₂—;-   Y is O;-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of Formula (I)wherein:

-   R₁ is hydroxy, aminocarbonyl, formylamino; phenyl-aminocarbonyl; or    phenyl(C₁₋₄)alkanylaminocarbonyl;-   R₂ is hydrogen, methyl, allyl, 3-methyl-but-2-enyl,    cyclopropylmethyl, phenylmethyl, or heteroarylmethyl wherein    heteroaryl is selected from the group consisting of    benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, and thienyl;-   A is —(CH₂)₂—;-   Y is O;-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of Formula (I)wherein:

-   R₁ is hydroxy, aminocarbonyl, formylamino; phenyl-aminocarbonyl; or    phenylmethylaminocarbonyl;-   R₂ is hydrogen, methyl, 3-methyl-but-2-enyl, cyclopropylmethyl,    phenylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl,    pyridin-4-ylmethyl, 2-hydroxy-pyridin-4-ylmethyl,    imidazol-2-ylmethyl, thien-2-ylmethyl, or furan-3-ylmethyl;-   A is —(CH₂)₂—;-   Y is O;-   and enantiomers, diastereomers, tautomers, solvates, or    pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is directed to compositionscomprising a compound of Formula (Ia)

selected from the group consisting of

-   a compound of Formula (Ia) wherein R₁ is methoxy, A is —(CH₂)₂—, and    R₂ is H;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is H;-   a compound of Formula (Ia) wherein R₁ is aminocarbonyl, A is    —(CH₂)₂—, and R₂ is H;-   a compound of Formula (Ia) wherein R₁is aminocarbonyl, A is    —(CH₂)₂—, and R₂ is furan-2-ylmethyl;-   Enant. A, a compound of Formula (Ia) wherein R₁ is hydroxy, A is    —(CH₂)₂—, and R₂ is trifluoromethylcarbonyl;-   Enant. B, a compound of Formula (Ia) wherein R₁ is hydroxy, A is    —(CH₂)₂—, and R₂ is trifluoromethylcarbonyl;-   a compound of Formula (Ia) wherein R₁ is methoxycarbonyl, A is    —(CH₂)₂—, and R₂ is trifluoromethylcarbonyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is H;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is H;-   a compound of Formula (Ia) wherein R₁ is methylaminocarbonyl, A is    —(CH₂)₂—, and R₂ is H;-   a compound of Formula (Ia) wherein R₁ is dimethylaminocarbonyl, A is    —(CH₂)₂—, and R₂ is H;-   a compound of Formula (Ia) wherein R₁ is phenyl-aminocarbonyl, A is    —(CH₂)₂—, and R₂ is H;-   a compound of Formula (Ia) wherein R₁ is phenylmethyl-aminocarbonyl,    A is —(CH₂)₂—, and R₂ is H;-   a compound of Formula (Ia) wherein R₁ is phenylethyl-aminocarbonyl,    A is —(CH₂)₂—, and R₂ is H;-   a compound of Formula (Ia) wherein R₁ is    (2-dimethylamino-ethyl)aminocarbonyl, A is —(CH₂)₂—, and R₂ is H;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is absent, and    R₂ is H;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₃—, and    R₂ is methyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is absent, and    R₂ is methyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is methyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₃—, and    R₂ is H;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is pyridin-2-ylmethyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is pyridin-4-ylmethyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is 2-hydroxy-pyridin-4-ylmethyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is thien-2-ylmethyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is furan-3-ylmethyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is cyclopropylmethyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is 2-methyl-but-2-enyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is 2-phenyl-imidazol-4-ylmethyl;-   a compound of Formula (Ia) wherein R₁ is aminocarbonyl, A is    —(CH₂)₂—, and R₂ is trifluoromethylcarbonyl-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is phenethyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is pyridin-2-ylmethyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is phenylmethyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is benzothien-3-ylmethyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH2)₂—, and    R₂ is 1H-imidazol-2-ylmethyl;-   a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and    R₂ is isoquinolin-5-ylmethyl;-   Enant. A, a compound of Formula (Ia) wherein R₁ is aminocarbonyl, A    is —(CH₂)₂—, and R₂ is trifluoromethylcarbonyl;-   Enant. A, a compound of Formula (Ia) wherein R₁ is aminocarbonyl, A    is —(CH₂)₂—, and R₂ is H;-   Enant. B, a compound of Formula (Ia) wherein R₁ is aminocarbonyl, A    is —(CH₂)₂—, and R₂ is trifluoromethylcarbonyl;-   Enant. A, a compound of Formula (Ia) wherein R₁ is aminocarbonyl, A    is —(CH₂)₂—, and R₂ is H;-   a compound of Formula (Ia) wherein R₁ is amino, A is —(CH₂)₂—, and    R₂ is H;-   a compound of Formula (Ia) wherein R₁ is hydroxyamidino, A is    —(CH₂)₂—, and R₂ is H;-   a compound of Formula (Ia) wherein R₁ is hydroxyamidino, A is    —(CH₂)₂—, and R₂ is H;-   a compound of Formula (Ia) wherein R₁ is formylamino, A is —(CH₂)₂—,    and R₂ is H;-   Enant. A, a compound of Formula (Ia) wherein R₁ is hydroxy, A is    —(CH₂)₂—, and R₂ is phenylmethyl;-   Enant. B, a compound of Formula (Ia) wherein R₁ is hydroxy, A is    —(CH₂)₂—, and R₂ is phenylmethyl;-   a compound of Formula (Ia) wherein R₁ is phenylaminocarbonyl, A is    —(CH₂)₂—, and R₂ is H;-   a compound of Formula (Ia) wherein R₁ is phenylaminocarbonyl, A is    —(CH₂)₂—, and R₂ is H;-   Enant, A, a compound of Formula (Ia) wherein R₁ is hydroxy, A is    —(CH₂)₂—, and R₂ is pyridin-3ylmethyl;-   Enant. B, a compound of Formula (Ia) wherein R₁ is hydroxy, A is    —(CH₂)₂—, and R₂ is pyridin-3-ylmethyl;-   Enant. A, a compound of Formula (Ia) wherein R₁ is hydroxy, A is    —(CH₂)₂—, and R₂ is methyl;-   Enant. B, a compound of Formula (Ia) wherein R₁ is hydroxy, A is    —(CH₂)₂—, and R₂ is methyl;-   Enant. A, a compound of Formula (Ia) wherein R₁ is    phenylmethylaminocarbonyl, A is —(CH₂)₂—, and R₂ is H;-   Enant. B, a compound of Formula (Ia) wherein R₁ is    phenylmethylaminocarbonyl, A is —(CH₂)₂—, and R₂ is H;-   Enant. A, a compound of Formula (Ia) wherein R₁ is    phenethylaminocarbonyl, A is —(CH₂)₂—, and R₂ is H;-   Enant. B, a compound of Formula (Ia) wherein R₁ is    phenethylaminocarbonyl, A is —(CH₂)₂—, and R₂ is H;-   Enant. B, a compound of Formula (Ia) wherein R₁ is hydroxy, A is    —(CH₂)₂—, and R₂ is furan-3-ylmethyl;-   Enant. A, a compound of Formula (Ia) wherein R₁ is hydroxy, A is    —(CH₂)₂—, and R₂ is furan-3-ylmethyl;-   Enant. A, a compound of Formula (Ia) wherein R₁ is hydroxy, A is    —(CH₂)₂—, and R₂ is pyridin-2-ylmethyl;-   Enant. B, a compound of Formula (Ia) wherein R₁ is hydroxy, A is    —(CH₂)₂—, and R₂ is pyridin-2-ylmethyl;-   a compound of Formula (Ia) wherein R₁ is 4-chloro-phenylamino, A is    —(CH₂)₂—, and R₂ is H;-   a compound of Formula (Ia) wherein R₁ is pyridin-3-ylamino, A is    —(CH₂)₂—, and R₂ is H; and-   a compound of Formula (Ia) wherein R₁ is phenylamino, A is —(CH₂)₂—,    and R₂ is H.

Another embodiment of the present invention is directed to compositionscomprising a compound of Formula (Ib)

selected from the group consisting of

-   a compound of Formula (Ib) wherein R₁ is aminocarbonyl, A is    —(CH₂)₂—, and R₂ is H; and-   a compound of Formula (Ib) wherein R₁ is aminocarbonyl, A is    —(CH₂)₂—, and R₂ is trifluoromethylcarbonyl.

Another embodiment of the present invention is a composition comprisingthe dextrorotatory enantiomer of a compound of formula (I), wherein saidcomposition is substantially free from the levorotatory isomer of saidcompound. In the present context, substantially free means less than25%, preferably less than 10%, more preferably less than 5%, even morepreferably less than 2% and even more preferably less than 1% of thelevorotatory isomer calculated as.

${\%\mspace{11mu}{levorotatory}} = {\frac{( {{mass}\mspace{20mu}{levorotatory}} )}{( {{mass}\mspace{14mu}{dextrorotatory}} ) + ( {{mass}\mspace{20mu}{levorotatory}} )} \times 100}$

Another embodiment of the present invention is a composition comprisingthe levorotatory enantiomer of a compound of formula (I) wherein saidcomposition is substantially free from the dextrorotatory isomer of saidcompound. In the present context, substantially free from means lessthan 25%, preferably less than 10%, more preferably less than 5%, evenmore preferably less than 2% and even more preferably less than 1% ofthe dextrorotatory isomer calculated as

${\%\mspace{11mu}{dextrorotatory}} = {\frac{( {{mass}\mspace{20mu}{dextrorotatory}} )}{( {{mass}\mspace{14mu}{dextrorotatory}} ) + ( {{mass}\mspace{20mu}{levorotatory}} )} \times 100}$

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts” (Ref International J. Pharm., 1986, 33, 201-217; J.Pharm.Sci., 1997 (Jan), 66, 1, 1). Other salts well known to those inthe art may, however, be useful in the preparation of compoundsaccording to this invention or of their pharmaceutically acceptablesalts. Representative organic or inorganic acids include, but are notlimited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric,nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic,maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.Representative hydroxy group prodrug forms include, but are not limitedto, C₁₋₄alkanylethers, substituted C₁₋₄alkanylethers, and C₁₋₄alkanylesters.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography, The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Even though the compounds of the present invention (including theirpharmaceutically acceptable salts and pharmaceutically acceptablesolvates) can be administered alone, they will generally be administeredin admixture with a pharmaceutical carrier, excipient or diluentselected with regard to the intended route of administration andstandard pharmaceutical or veterinary practice. Thus, the presentinvention is directed to pharmaceutical and veterinary compositionscomprising compounds of Formula (I) and one or more pharmaceuticallyacceptable carriers, excipients or diluents.

By way of example, in the pharmaceutical and veterinary compositions ofthe present invention, the compounds of the present invention may beadmixed with any suitable binder(s), lubricant(s), suspending agent(s),coating agent(s), and/or solubilising agent(s).

Tablets or capsules of the compounds may be administered singly or twoor more at a time, as appropriate. It is also possible to administer thecompounds in sustained release formulations.

Alternatively, the compounds of the general Formula (I) can beadministered by inhalation or in the form of a suppository or pessary,or they may be applied topically in the form of a lotion, solution,cream, ointment or dusting powder. An alternative means of transdermaladministration is by use of a skin patch. For example, they can beincorporated into a cream consisting of an aqueous emulsion ofpolyethylene glycols or liquid paraffin. They can also be incorporated,at a concentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstabilizers and preservatives as may be required.

For some applications, preferably the compositions are administeredorally in the form of tablets containing excipients such as starch orlactose, or in capsules or ovules either alone or in admixture withexcipients, or in the form of elixirs, solutions or suspensionscontaining flavoring or coloring agents.

The compositions (as well as the compounds alone) can also be injectedparenterally, for example intracavernosally, intravenously,intramuscularly or subcutaneously. In this case, the compositions willcomprise a suitable carrier or diluent.

For parenteral administration, the compositions are best used in theform of a sterile aqueous solution which may contain other substances,for example enough salts or monosaccharides to make the solutionisotonic with blood.

For buccal or sublingual administration the compositions may beadministered in the form of tablets or lozenges which can be formulatedin a conventional manner.

By way of further example, pharmaceutical and veterinary compositionscontaining one or more of the compounds of the invention describedherein as the active ingredient can be prepared by intimately mixing thecompound or compounds with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques The carrier may takea wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate the major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those skilled in that art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedand will vary with the particular compound used, the mode ofadministration, the strength of the preparation, and the advancement ofthe disease condition. In addition, factors associated with theparticular subject being treated, including subject age, weight, dietand time of administration, will result in the need to adjust the doseto an appropriate therapeutic level. The above dosages are thusexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as analgesics is required for a subject in need thereof.

The invention also provides a pharmaceutical or veterinary pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical and veterinary compositions of theinvention. Optionally associated with such container(s) can be a noticein the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals or biological products,which notice reflects approval by the agency of manufacture, use or salefor human administration.

The compounds of the present invention may be used to treat mild tosevere pain in warm-blooded animals such as humans by administration ofan analgesically effective dose. The dosage range would be from about0.1 mg to about 15,000 mg, in particular from about 50 mg to about 3500mg or, more particularly from about 100 mg to about 1000 mg of activeingredient in a regimen of about 1 to 4 times per day for an average (70kg) human; although, it is apparent to one skilled in the art that thetherapeutically effective amount for active compounds of the inventionwill vary as will the types of pain being treated.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing 0.01, 10.0, 50.0, 100, 150,200, 250, and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the subject to be treated.

Examples of pain intended to be within the scope of the presentinvention include, but are not limited to, inflammatory pain, centrallymediated pain, peripherally mediated pain, visceral pain, structural orsoft tissue injury related pain, progressive disease related pain,neuropathic pain and acute pain such as caused by acute injury, traumaor surgery and chronic pain such as headache and that caused byneuropathic conditions, post-stroke conditions, cancer, and migraine.

Compounds of the present invention are also useful asimmunosuppressants, antiinflammatory agents, agents for the treatmentand prevention of neurological and psychiatric conditions, for instance,depression and Parkinson's disease, agents for the treatment ofurological and reproductive conditions, for instance, urinaryincontinence and premature ejaculation, medicaments for drug and alcoholabuse, agents for treating gastritis and diarrhea, cardiovascular agentsand cardioprotective agents and agents for the treatment of respiratorydiseases.

The compounds of the present invention are also useful in treating paincaused by osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine,headache, toothache, burn, sunburn, snake bite (in particular, venomoussnake bite), spider bite, insect sting, neurogenic bladder, benignprostatic hypertrophy, interstitial cystitis, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, cellulites, causalgia, sciatic neuritis, mandibular jointneuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limbpain, post-operative ileus, cholecystitis, postmastectomy pain syndrome,oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy,Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome,post-herpetic neuralgia, trigeminal neuralgia, cluster headache,migraine headache, peripheral neuropathy, bilateral peripheralneuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminalneuralgia, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, inflammatory boweldisease, irritable bowel syndrome, sinus headache, tension headache,labor, childbirth, menstrual cramps, and cancer.

In regard to the use of the present compounds in treatment of thedisases or conditions such as those listed above, a therapeuticallyeffective dose can be determined by persons skilled in the art by theuse of established animal models. Such a dose would likely fall in therange of from about 0.01 mg to about 15,000 mg of active ingredientadministered 1 to 4 times per day for an average (70 kg) human.

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated in the schemes that follow. Since the schemes are anillustration, the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The preparation of thevarious starting materials used in the schemes is well within the skillof persons versed in the art.

The preparation of compounds of this invention wherein R₁ is OH isillustrated in Scheme 1. Compounds in which R₁ is SH may be prepared inan analogous manner, starting with a thioether, such as amethylthioether, wherein R is methyl. In stages 1.1 and 1.2,intermediates 1C and 2 consist of two functionalized benzene ringsconnected by a linker —Y—, wherein Y is defined as oxygen or sulfur. Onebenzene ring must bear a carboxylic acid, or a precursor to a carboxylicacid, positioned ortho to the linker —Y—.

In Scheme 1 Stage 1.1, the —Y— bridge may be constructed from compounds1A and 1B by a nucleophilic aromatic displacement of an appropriateleaving group X, wherein X is fluoro, chloro, bromo, iodo, or the like.The compounds of formula 2 are then obtained by hydrolysis of the R₁₁ester (wherein R₁₁, is a C₁₋₄alkanyl) of compounds of formula 1C with analkali metal hydroxide (Stage 1.2).

In Stage 1.3 compounds of formula 2 are converted by cycloacylation toketones of formula 3, using, for instance, BF₃.Et₂O-trifluoroaceticanhydride or polyphosphoric acid. Alternatively, the cyclization may beeffected by converting the acid functionality of compounds of formula 2to an acid chloride, for instance with thionyl chloride or oxalylchloride, followed by Friedel-Crafts ring closure in the presence of aLewis acid, such as aluminum chloride.

To perform Stage 1.4, the ketone is replaced by an appropriatelysubstituted alkenyl functionality to give compounds of formula 4. Thistransformation may be carried out by a McMurray condensation of theketones of formula 3 with a second appropriate ketone in the presence ofa lower valent titanium reagent such as the reagent obtained fromaddition of titanium tetrachloride to zinc dust. Alternatively, anappropriately substituted magnesium halide may be added to ketones offormula 3 to afford carbinols. Dehydration of such carbinols with acidicreagents such as formic acid, sulfuric acid or trifluoroacetic acidgives rise to compounds of formula 4.

Stage 1.5 includes the removal of R (wherein R is C₁₋₄alkanyl or benzyl)from compounds of formula 4 using conventional deprotection methods.Such transformations may include the dealkylation of lower alkyl ethersto give their corresponding alcohols, using reagents such as borontrihalides or removal of the benzyl group via hydrogenation usinghydrogen gas and a transition metal catalyst such as palladium. In thecase of methylthioethers, demethylation of the methyl thiol may beaccomplished via treatment with meta-chloroperbenzoic acid, followed byheating in trifluoroacetic anhydride.

As illustrated in Scheme 1, the nitrogen atoms of compounds of formula 4and 5 may bear a group P. This group may be an alkanyl, alkenyl oraralkanyl in which case they are therapeutically useful products of thisinvention. The group P may also be trifluoromethylcarbonyl,alkoxycarbonyl or aralkoxycarbonyl. The group P can be removed toproduce free amine 6 (Stage 1.6). This transformation may be carried outusing certain acidic reagents such as trifluoroacetic acid, hydrogenbromide, or trimethylsilyl iodide. Or, when P is atrifluoromethylcarbonyl, basic reagents such as potassium carbonate inan alcoholic solvent may be used for the removal of P. Compounds offormula 4 and 5 bearing readily cleavable groups such as methyl, allylor benzyl may be transformed into the aforementioned alkoxycarbonylderivatives by treatment with alkanylchloroformates such as ethylchloroformate or 1-chloroethyl chloroformate.

Finally, the secondary amines of formula 6 may be converted to compoundsof formula (I)-1as shown in Stage 1.7. These transformations may becarried out by reductive alkylation with a carbonyl compound in thepresence of a reducing agent such as sodium borohydride, sodiumcyanoborohydride, sodium triacetoxyborohydride, or tetramethylammoni urntriacetoxyborohydride. Alternatively, the amines of formula 6 may betreated with an appropriate alkylating agent, such as a halide- ortosylate-substituted alkanyl, alkenyl or aralkyl group and an organic orinorganic base.

Finally, the transformation of compounds of formula 4 into compounds offormula (I)-1 may also be accomplished by reversing the order of Stages1.5 and Stage 1.6. In this case, group P is removed prior to removal ofR by the methods described above.

Scheme 2 demonstrates the preparation of compounds of the presentinvention wherein R₁ is other than hydroxy or mercapto. A compound offormula 5 can be converted to its triflate by treatment withN,N-bis(trifluoromethylsulfonyl)phenylamine or similar reagents toafford a compound of formula 2A. Treatment of the triflate with acyanide source such as zinc cyanide in the presence of a palladiumcatalyst provides compounds of formula 2B, which subsequently can behydrolyzed with hydroxide anion in the presence of hydrogen peroxide toafford compounds of formula (I)-2 wherein R₁ is an aminocarbonyl.

The cyano group of a compound of formula 2B is also a precursor to otherR₁ substituents of the present invention. For example, a compound offormula 2B can be treated with ammonium hydroxide in the presence of abase such as a tertiary amine to afford a hydroxyamidino compound offormula (I)-3.

Similarly, a compound of formula 5 may be treated with amino synthon,wherein a synthon is a synthetic equivalent or a functional group thatis related to some other structural unit by a reliable reaction orsequence of reactions. An example of an amino group synthon includes,but is not limited to, benzophenone imine. Benzophenone imine may beused in the presence of an appropriate palladium catalyst under basicconditions, which upon treatment with ammonium hydroxide, affordscompounds of formula 3A. The aniline may be formylated with aceticformic anhydride to give compounds of formula (I)-4, followed by removalof P using methods discussed herein. Lawesson's reagent may be used toconvert carbonyl-containing R₁ substituents to their correspondingthiocarbonyl analogs.

The preparation of compounds wherein R₁ is C₆₋₁₀arylamino can beachieved using a palladium catalyzed amination of a compound of formula2A with C₆₋₁₀arylamine and an inorganic base, such as cesium carbonate.

Anilines of formula 3A may be converted to the correspondingaminothiazoles of formula (I)-5 via reaction with appropriate reagentssuch as potassium thiocyanate.

The preparation of compounds of this invention wherein R₁ is acarboxamide is illustrated in Scheme 5. In Stage 5.1, the —Y— bridge maybe constructed from compounds 5A (wherein X₁ is a bromo or chlorosubstituent) and 5B by a nucleophilic aromatic displacement of anappropriate leaving group X₂, wherein X₂ is fluoro, chloro, bromo, iodo,or the like. The thus obtained intermediate 5C consists of twofunctionalized benzene rings connected by an oxygen or sulfer linker,—Y—. One benzene ring must bear a precursor to a carboxamide such as anitrile or a carboxylic acid, positioned ofthoto the linker —Y—, and theother benzene ring must bear a halogen such as bromine (hereinrepresented as X₁), positioned ortho to —YH, that can later be convertedto a carboxamide. The compounds of formula 5D are then obtained byhydrolysis of the nitrile of compounds of formula 5C (Stage 5.2) whilein the presence of an alkali metal hydroxide.

The conversion of compounds of type 5D to compounds of type 5E can beaccomplished as previously described in Stage 1.3, using, for instance,BF₃.Et₂O-trifluoroacetic anhydride or polyphosphoric acid.Alternatively, the cyclization may be effected by converting the acidfunctionality of compounds of formula 5D to an acid chloride, forinstance with thionyl chloride or oxalyl chloride, followed byFriedel-Crafts ring closure in the presence of a Lewis acid, such asaluminum chloride.

To perform Stage 5.3, the halogen X₁ is converted to a carboxamide,wherein R_(a) and R_(b) are each hydrogen or C₁₋₄alkanyl. Halogen X₁ maybe converted to an ester via alkoxycarbonylation using carbon monoxide,an aliphatic alcohol, a trialkanyl amine, and a palladium catalyst suchas bis(triphenylphosphine) palladium(II)dichloride. Subsequently, thethus obtained ester may be hydrolyzed to a carboxylic acid and coupledwith ammonia, a primary amine, or a secondary amine to form a primary,secondary or tertiary amide, respectively. Alternatively, the conversionof a carboxylic acid to an amide may be carried out via an acid chlorideusing thionyl chloride, oxalyl chloride, or the like, followed by aSchotten-Baumann reaction using ammonia or an amine in the presence ofan alkali metal hydroxide. Alternatively, the ester may be converteddirectly to the amide by the action of a dimethylaluminum amide.Finally, the halogen X₁ can be displaced with a cyano group, which canthen be hydrolyzed to the corresponding amide or acid.

The conversion of compounds of formula 5F to compounds of formula (I)-5can be accomplished by performing Stages 1.4, 1.6 and 1.7 as describedfor Scheme 1.

The preparation of compounds of this invention wherein R₁ isC₆₋₁₀arylamino or pyridinylamino is illustrated in Scheme 6, (R_(1A) isa C₆₋₁₀aryl or pyridinyl). In Stage 6.1, the —Y— bridge may beconstructed from compounds 6A and 6B by a nucleophilic aromaticdisplacement of an appropriate leaving group X₂, as previously definedherein. The thus obtained intermediate 6C consists of two functionalizedbenzene rings connected by an oxygen or sulfur linker —Y—. One benzenering must bear a precursor to an amine such as a nitro group, positionedortho to the linker —Y—, and a carboxylic acid or equivalent such asnitrite, also positioned ortho to the linker —Y—.

The conversion of compounds of formula 6C to compounds of formula 6D canbe accomplished as previously described in Stage 1.3, using, forinstance, BF₃.Et₂O-trifluoroacetic anhydride or polyphosphoric acid.Alternatively, the cyclization may be effected by converting the acidfunctionality of compounds of formula 6C to an acid chloride, forinstance with thionyl chloride or oxalyl chloride, followed byFriedel-Crafts ring closure in the presence of a Lewis acid, such asaluminum chloride.

The conversion of compounds of formula 6D to compounds of formula 6E canbe accomplished via catalytic reduction of the nitro group to thecorresponding amine using standard hydrogenation conditions in thepresence of palladium metal. Installation of an R_(1A) substituent canbe accomplished via transition metal-mediated coupling reactions witharyl halides or pyridinyl halides in the presence of a suitable catalystsuch as Pd₂(dba)₃ or the like, a suitable ligand such as Xanthphos orthe like, and a base, such as potassium tert-butoxide or cesiumcarbonate.

The conversion of compounds of formula 6F to compounds of formula (I)-6can be accomplished by performing Stages 1.4, 1.6 and 1.7 as describedfor Scheme 1.

Compounds of Formula (I) that are chiral may be separated into theirenantiomers by chromatography on a chiral stationary phase followingStages 1.4, through 1.7. Alternatively, the basic compounds of thepresent invention may be converted to diastereomeric salts by mixturewith a chiral acid and resolved into their enantiomers by fractionalcrystallization.

It is generally preferred that the respective product of each processstep be separated from other components of the reaction mixture andsubjected to purification before its use as a starting material in asubsequent step. Separation techniques typically include evaporation,extraction, precipitation and filtration. Purification techniquestypically include column chromatography (Still, W. C. et. al., J. Org.Chem. 1978, 43, 2921), thin-layer chromatography, crystallization anddistillation. The structures of the final products, intermediates andstarting materials are confirmed by spectroscopic, spectrometric andanalytical methods including nuclear magnetic resonance (NMR), massspectrometry (MS), circular dichroism (CD), and liquid chromatography(HPLC). In the descriptions for the preparation of compounds of thisinvention, ethyl ether, tetrahydrofuran and dioxane are common examplesof an ethereal solvent; benzene, toluene, hexanes and heptanes aretypical hydrocarbon solvents and dichloromethane and dichloroethane arerepresentative halogenated hydrocarbon solvents. In those cases wherethe product is isolated as the acid addition salt the free base may beobtained by techniques known to those skilled in the art. In those casesin which the product is isolated as an acid addition salt, the salt maycontain one or more equivalents of the acid. Enantiomers of thecompounds of the present invention may be separated using chiral HPLC.CD spectra were generated on a Jasco J-710 spectropolarimeter. Specificconditions were as follows: cell length: 0.1 cm; concentration: 0.238Min methanol); temperature: 25° C.; Ch2-mode: HT voltage; Range 350-200nm; Band with: 1.0 nm; Sensitivity: 20 mdeg; Resolution: 0.2 nm;Response: 2 sec; Speed: 100 nm/min; Accumulation: 2 scans.

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described above and areillustrated more particularly in the schemes that follow. Since theschemes are illustrations, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

Abbreviations CD = circular dichroism DMF = N,N-dimethylformamide dppf =diphenylphosphinoferrocene h/hr = hour(s) Me = methyl min = minute(s)PPA = polyphosphoric acid t-Boc = tert-butoxycarbonyl TFA =trifluoroacetic acid THF = tetrahydrofuran

EXAMPLES Examples A

Procedure 1

2-(2-Methoxy-phenoxy)-benzoic acid, 1a

Tetrakis(acetonitrile)copper(I) hexafluorophosphate (4.62 g, 12.4 mmol),cesium carbonate (32 g, 98 mmol), 2-bromobenzoic acid (10g, 49. 7 mmol)and 2-methoxyphenol (6.17 g, 49.7 mmol) were combined in toluene (100mL), and the mixture was heated to reflux for 15 hr. Ethyl acetate (200mL) and 1N HCl (200 mL) were added, and the organic layer was separated.The organic layer was dried over MgSO₄, filtered, and evaporated toyield 16.8 g of Compound 1a. The residue was used without furtherpurification. MS m/z (M-H)⁻ 243.1.

Procedure 2

4-Methoxy-xanthen-9-one, 2a

To a suspension of 2-(2-methoxy-phenoxy)-benzoic acid (16.8 g, 68.8mmol) in methylene chloride (100 mL) at 0° C. was added dropwisetrifluoroacetic anhydride (12.7 mL, 89.4 mmol), and the reaction wasstirred for 30 min at 0° C. At that time, boron trifluoride diethyletherate (1.29 mL, 10.3 mmol) was added dropwise. The reaction wasstirred overnight at rt, poured into H₂O, and washed with brine. Theorganic phase was dried over MgSO₄, filtered, and concentrated to give12.4 g (54.8 mmol) of Compound 2a.

Procedure 3

4-Hydroxy-xanthen-9-one, 3a

To a solution of 4-methoxy-xanthen-9-one (12 g, 53 mmol) in methylenechloride (100 mL) at 0° C. was added a 1M solution of boron tribromidein methylene chloride (160 mL, 160 mmol) and the mixture was stirred atrt for 2 h. The reaction was slowly poured into a solution of ammonia inmethanol (2M). The reaction was concentrated under reduced pressure andthe resulting residue was partitioned between 1N HCl and methylenechloride. The organic phase was separated, dried over MgSO₄, filtered,and evaporated to afford 7.5 g of Compound 3a, without furtherpurification. MS m/z (M-H)⁻ 243.1.

Procedure 4

2,2,2-Trifluoro-1-[3-(4-hydroxy-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethanone,4a

A suspension of zinc metal dust (16.9 g, 259 mmol) in THF (150 mL) underArgon at 5° C. was treated dropwise with titanium (IV) tetrachloride(14.3 mL, 130 mmol). The reaction was refluxed for 2 h. The heat wasremoved and 4-hydroxy-xanthen-9-one (6.92 g, 46 mmol) andN-trifluoroacetyl-nortropinone (7.18 g, 32.5 mmol) were added, Thereaction was refluxed for another 2 h. The reaction was cooled,filtered, and evaporated. The residue was partitioned inchloroform:ethyl acetate and 1N HCl. The organic phase was separated,dried, over MgSO₄, filtered and evaporated to give 13.22 g of Compound4a. MS m/z=402.0 (MH⁺).

Procedure 5

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol, Cpd 2

Potassium carbonate (7.21 g, 52 mmol) was added to a solution ofCompound 4a (7.27 g, 18 mmol) in methanol (60 mL), and the reaction wasstirred overnight. The reaction was filtered and then ion exchange resinwas added (100 g, AG 50W-X210) and the reaction stirred 1 h. The resinwas collected by filtration and washed sequentially with water (50 mL)and then methanol (50 mL). The resin was then treated with ammonia inmethanol (2M, 500 mL) for 1 h before being collected by filtrationagain. The filtrate was concentrated under reduced pressure to affordCompound 2 (2.1 g).Procedure 6

9-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol,Cpd 25

A portion of 9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-oltrifluoroacetate salt (0.10 g, 0.23 mmol), 3-furaldehyde (0.025 g, 0.26mmol), triethylamine (0.036 g, 0.35 mmol, Aldrich), and sodiumtriacetoxyborohydride (0.065 g, 0.30 mmol) were stirred in THF (4 mL)overnight. The solvent was evaporated and the residue dissolved inmethanol (3 mL) and 1N aqueous HCl (1 mL). The solution was injectedonto a prep reverse phase HPLC. The appropriate fractions werelyophilized to afford9-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol(0.046 g, 0.11 mmol, 50% yield, MH⁺ 386.17).

Example B

Procedure 7

Trifluoromethanesulfonic acid9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthen-4-ylester, 1b

2,2,2-Trifluoro-1-[3-(4-hydroxy-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethanonemay be dissolved in methylene chloride (0.1M to 2 M solution), cooled to0° C., and trifluoromethane sulfonic anhydride (1.0 to 1.5 equiv) andtriethylamine (1.0 to 2 equiv) may be added dropwise. The solution maybe stirred at 0° C. to room temperature for 1 to 5 hrs. After aqueousworkup, drying over a suitable drying agent such as sodium sulfate ormagnesium sulfate, and evaporation of solvent, Compound 1b may beobtained.

Procedure 8

9-[8-(2,2,2-Trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carbonitrile,2b

A solution of trifluoromethanesulfonic acid 9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthen-4-ylester in a deoxygenated solvent such as dimethyl formamide (0.5 to 2 Msolution) may be treated with a catalytic amount of a palladium catalystsuch as tetrakis(triphenylphosphine) palladium ( 0.01 to 0.1 equiv) anda cyanide source such as zinc cyanide (1.5 to 3 equiv). The mixture maybe heated to 100° C. to 150° C. under an argon atmosphere for 1 to 5 hr.After cooling, the mixture may be partitioned between a saturated sodiumbicarbonate solution and an organic solvent such as ethyl acetate. Theorganic phase may be separated, dried over an appropriate drying agentsuch as sodium sulfate, filtered, and evaporated. The residue may bepurified over silica gel using a mixture of organic solvents or viareverse phase chromatography to yield Compound 2b.

Procedure 9

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acidamide, Cpd 3

9-[8-(2,2,2-Trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carbonitrilemay be dissolved in an alcoholic solvent such as methanol (0.05 to 1 M)and treated with a concentrated potassium hydroxide solution (20 to 30%)and a catalytic amount (2 to 5 drops) of hydrogen peroxide solution. Themixture may be heated to reflux for 1 to 6 hr. After cooling, thesolution may be extracted with an organic solvent such as ethyl acetate.The organic phase may be dried over a suitable drying agent such aspotassium carbonate, filtered, and evaporated. The crude product may bepurified via reverse phase column chromatography to yield Compound 3.

9-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylicacid amide, 3b

Following Procedure 6, substituting9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acidamide for 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol and2-pyridylcarboxaldehyde for 3-furaldehyde, Compound 3b may be obtained.

Example C

Procedure 10

1-{3-[4-(Benzhydrylidene-amino)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]oct-8-yl}-2,2,2-trifluoroethanone,1c

A solution of trifluoromethanesulfonic acid9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3ylidene]-9H-xanthen-4-ylester in THF (0.1 to 1 M solution) may be treated with a catalyticamount of a palladium catalyst such as palladium acetate (0.01 to 0.05equiv), BINAP (0.01 to 0.05 equiv), benzophenone imine (1.05 to 1.5equiv), and cesium carbonate (1.2 to 2 equiv) under an argon atmosphere.The mixture may be heated to reflux for a period of 10 to 24 hr. Afterremoval of the solvent via evaporation, the residue may be taken up in ahalogenated solvent such as methylene chloride, and the solution may bewashed with water, dried over a suitable drying agent such as magnesiumsulfate, filtered, and concentrated. The residue may be purified viacolumn chromatography to yield Compound 1c.

Procedure 11

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ylamine, 2c

A solution of1-{3-[4-(benzhydrylidene-amino)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]oct-8-yl}-2,2,2-trifluoroethanonein methanol (0.1 to 1 M solution) may be treated with sodium acetate (2to 4 equiv) and hydroxylamine hydrochloride (1 to 3 equiv) and stirredat rt for 1 to 4 days. Sodium hydroxide may be added to make thesolution basic, and the solution may be stirred at rt for 1 to 5 hr.Methylene chloride and water may be added, and the organic layer may beseparated. After drying over a suitable drying agent such as potassiumcarbonate, filtration, and evaporation, the residue may be purified viareverse phase column chromatography to yield Compound 2c.

Procedure 12

9-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ylamine, 3c

Following Procedure 6, substituting9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ylamine for9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol and benzaldehydefor 3-furaldehyde, Compound 3c may be obtained.

Procedure 13

N-[9-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-yl]-formamide,4c

Equimolar amounts of acetic anhydride and formic acid may be combined at0° C. and heated to 50-60° C. for 2 hr to produce acetic formicanhydride. The mixture may be cooled to or below 0° C. and9-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ylamine maybe added. After stirring at) 0° C. for a period of 15 min to 2 hr, themixture may be evaporated to yield Compound 4c.

Example D

Procedure 14

2,2,2-Trifluoro-1-[3-(4-phenylamino-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethanone,1d

A solution of trifluoromethanesulfonic acid9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthen-4-ylester in toluene (0.1 to 2 M solution) may be treated with a catalyticamount of a palladium catalyst such as Pd₂(dba)₃ (0.01 to 0.1 equiv),DPPF (0.1 to 0.3 equiv), aniline (2 to 5 equiv), sodium tert-butoxide(1.2 to 2 equiv) under an argon atmosphere. The mixture may be heated to80° C. for a period of 1 to 10 hr. After filtration and removal of thesolvent via evaporation, the residue may be taken up in a halogenatedsolvent such as methylene chloride, and the solution may be washed withwater, dried over a suitable drying agent such as magnesium sulfate,filtered, and concentrated. The residue may be purified via columnchromatography to yield Compound 1d.

[9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-yl]-phenylamine, 2d

Following Procedure 5, substituting2,2,2-trifluoro-1-[3-(4-phenylamino-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethanonefor 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol, Compound 2dmay be obtained.

[9-(8-Furan-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-yl]-phenylamine,3d

Following Procedure 6, substituting[9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-yl]-phenylamine for9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol and 2-furaldehydefor 3-furaldehyde, Compound 3d may be obtained.

Example E

Procedure 15

9-[8-(2,2,2-Trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxylicacid methyl ester, 1e

A solution of trifluoromethanesulfonic acid9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthen-4-ylester in deoxygenated DMSO (0.1 to 1 M solution) may be treated with acatalytic amount of a palladium catalyst such as Pd(OAc)₂ (0.01 to 0.1equiv), bis(diphenylphosphino)ethane (0.01 to 0.1 equiv), methanol (100to 1000 equiv), triethylamine (1.1 to 2 equiv) and purged with CO bybubbling a stream of CO gas through the solution for 5 min. The mixturemay be heated to 80° C. for a period of 1 to 10 hr. After cooling, themixture may be partitioned between equal amounts of water and an organicsolvent such as ethyl acetate. The organic layer may be separated, driedover an appropriate drying agent such as magnesium sulfate, filtered,and evaporated. The residue may be purified via column chromatography toyield Compound 1e.

Procedure 16

[9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-yl]-methanol, 2e

A solution of9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxylicacid methyl ester in methylene chloride (0.001 to 1 M solution) at −78°C. may be treated with diisobutyl aluminum hydride (1M in cyclohexane; 2to 10 equiv), and the mixture may be allowed to slowly warm up to 0° C.After stirring at that temperature for a period of 1 to 5 hr, an aqueoussolution of Rochelle's salt may be added. The mixture may be extractedwith an appropriate organic solvent such as ethyl acetate, and theorganic layer may be dried over a suitable drying agent such aspotassium carbonate. After filtration and evaporation, the residue maybe purified via reverse phase column chromatography to yield Compound2e.

[9-(8-Furan-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-yl]-methanol,3e

Following Procedure 6, substituting[9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-yl]-methanol for9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol and 2-furaldehydefor 3-furaldehyde, Compound 3e may be obtained.

Example F

Procedure 17

N-Hydroxy-9-[8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxamidine,1f

A solution of9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carbonitrilein ethanol (0.1 to 2 M solution) may be treated with hydroxylaminehydrochloride (1 to 2 equiv) and triethylamine (2 to 3 equiv) and may beheated to reflux for a period of 1 to 10 hr. After cooling, the mixturemay be evaporated under reduced pressure, and the residue may bepartitioned between equal amounts of water and an organic solvent suchas ethyl acetate. The organic layer may be separated, dried over anappropriate drying agent such as magnesium sulfate, filtered, andevaporated. The residue may be purified via column chromatography toyield Compound 1f.

9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-N-hydroxy-9H-xanthene-4-carboxamidine,2f

Following Procedure 5, substitutingN-Hydroxy-9-[8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxamidinefor 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol, Compound 2fmay be obtained.

9-(8-Furan-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-N-hydroxy-9H-xanthene-4-carboxamidine,3f

Following Procedure 6, substituting9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-N-hydroxy-9H-xanthene-4-carboxamidinefor 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol and2-furaldehyde for 3-furaldehyde, Compound 3f may be obtained.

Example G

Procedure 18

N-Hydroxy-9-[8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxamidine,1g

To a solution of9-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylicacid amide in toluene (0.05 to 1 M solution), Lawesson's reagent (1.2 to2 equiv) may be added, and the mixture may be irradiated in a microwaveoven for 5 to 20 min, An organic solvent may be added to the cooledmixture, and the solution may be washed with an equal amount of water.The organic layer may be separated, dried over a suitable drying agentsuch as sodium sulfate, filtered, and evaporated. The residue may bepurified via reverse phase column chromatography to yield Compound 1g.

Example H

Procedure 19

6-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-6H-11-oxa-3-thia-1-aza-cyclopenta[a]anthracen-2-ylamine,1h

To a solution of9-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ylamine inglacial acetic acid (0.1 to 1 M solution) may be added potassiumthiocyanate (2 equiv). A solution of bromine (1 equiv) in glacial aceticacid (0.5 to 2 M solution) may be added slowly, and the resultingmixture may be stirred at rt for 1 to 4 hr. The solution may be basifiedwith a sodium hydroxide solution (5 to 20%), and extracted with asuitable organic solvent such as ethyl acetate. The organic layer may beseparated, dried over sodium sulfate, filtered, and evaporated. Theresidue may be purified via column chromatography to yield Compound 1h.

Example I

Enantiomers 5 and 6 in Table 1 herein were obtained via chiralseparation of the racemic material. The chiral separation was performedon a preparative Daicel Chiralpak® AD column (Amylosetris-(3,5-dimethylphenylcarbamate, coated on 20 μm silica gel; 500 gram;5 cm ID; 41 cm length) using an isocratic mixture ofheptane/methanol/ethanol (80/10/10) as eluent. The analytes weremonitored using a wavelength of 220 nm. Compounds 8 and 9 were obtainedvia deprotection of compounds 5 and 6, respectively.

Example J

Procedure 20

2-(2-Bromophenoxy)-benzonitrile, 1j

To a solution of 2-bromophenol (6.0 mL, 51.7 mmol) in DMF (80 mL) wasadded potassium carbonate (7.16 g, 51.7 mmol), and the mixture wasallowed to stir for 10 min ar rt. 2-Fluorobenzonitrile (5.62 mL, 82.6mmol) was added and the mixture was heated to 100° C. for 40 h. Themixture was allowed to cool to rt, poured onto ice, filtered, washedwith water, and dried to yield 13.0 g (91.7%) of title compound2-(2-bromophenoxy)-benzonitrile 1j.

Procedure 21

2-(2-Bromophenoxy)-benzoic acid, 2j

To a solution of compound 2-(2-bromophenoxy)-benzonitrile 1j (12.8 g,46.7 mmol) in ethanol (150 mL) was added a 3N sodium hydroxide solution(15 mL), and the mixture was heated to reflux for 16 h. The mixture wasallowed to cool to rt and evaporated. The residue was diluted withwater, and concentrated hydrochloric acid was added dropwise until themixture was acidic. The solid was separated via filtration, washed withwater, and dried to yield 12.8 g (93.5%) of title compound 2j.

Procedure 22

4-Bromo-xanthen-9-one, 3j

To a solution of 2-(2-bromophenoxy)-benzoic acid 2j (11.8 g, 40.3 mmol)in dichloromethane (200 mL) was added trifluoroacetic anhydride (6.3 mL,44.6 mmol), and the mixture was stirred for 30 min at rt. Borontrifluoride etherate (0.51 mL, 4.03 mmol) was added, and the mixture wasstirred for 2 h at rt. The mixture was cooled in an ice bath, and a 3Nsodium hydroxide solution (100 mL) was added under vigorous stirring.The organic layer was separated, washed with water and brine, dired overmagnesium sulfate, filtered, and evaporated. The residue was purifiedover silica gel using dichloromethane as eluent. The desired fractionswere collected, and evaporated to yield 10.18 g (91.8%) of titlecompound 3j.

Procedure 23

9-Oxo-9H-xanthene-4-carboxylic acid methyl ester, 4j

To a solution of 4-bromo-xanthen-9-one 3j (10 g, 36.35 mmol) andtriethylamine (15.2 mL, 109 mmol) in a mixture of dimethylformamide (80mL) and methanol 940 mL) was added PdCl₂(dppf).CH₂Cl₂ (3 g, 3 mmol), andsparged with carbon monoxide. The mixture was heated for 2 days at 80°C., poured into water, and the solid was collected via filtration. Thesolid was washed with water, air-dried, and dissolved indichloromethane. The solution was filtered, dried over magnesiumsulfate, filtered, and evaporated. The residue was purified via flashcolumn chromatography (eluent gradient: 0.2% to 3% methanol indichloromethane to yield 8.0 g (86.6%) of title compound 4j.

Procedure 24

9-Oxo-9H-xanthene-4-carboxylic acid, 5j

To a suspension of 9-oxo-9H-xanthene-4-carboxylic acid methyl ester 4j(2.0 g, 7.87 mmol) in methanol (30 mL) was added a 3N sodium hydroxidesolution (3.2 mL), and the mixture was heated to reflux for 2 h. Thesolvent was evaporated and the residue was dissolved in water (50 mL).The solution was filtered, acidified with concentrated hydrochloricacid, and a precipitate formed. The solid was separated via filtration,washed with water, and air-dried to yield 1.9 g (quant.) of titlecompound 5j.

Procedure 25

9-Oxo-9H-xanthene-4-carboxylic acid amide, 6j

To a solution of 9-oxo-9H-xanthene-4-carboxylic acid 5j (1.84 g, 7.66mmol) in dimethylformamide (20 mL) was addedN,N-diisopropyl-N-ethylamine (1.74 mmol, 9.96 mmol) andO(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate(2.9 g, 7.66 mmol). The mixture was stirred for 30 min at rt, andammonium hydroxide (2 mL) was added. The mixture was stirred for 3 h,poured onto ice, and the solid was collected via filtration. The solidwas washed with water and air-dried to yield 1.78 g (97.2% of titlecompound 6j.

9-[8-(2,2,2-Trifluoroacetyl)-8-azabicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxylicacid amide, 7j

Using an adaptation of the method described in Procedure 4, substitutingcompound 6j for compound 3a, the title compound 7j was obtained.

9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acidamide, Cpd 3

Using an adaptation of the method described in Procedure 5, substitutingcompound 7j for compound 4a, the title compound 3 was obtained as a TFAsalt.

9-(8-Furan-3-ylmethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylicacid amide, Cpd 4

Using an adaptation of the method described in Procedure 6, substituting9-(8-azabicyclo[3.2.1 ]oct-3-ylidene)-9H-xanthene-4-carboxylic acidamide for the trifluoroacetate salt of compound 2, the title compound 4was obtained as a TFA salt.

Procedure 26

(+)-9-[8-(2,2,2-Trifluoroacetyl)-8-azabicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxylicacid amide (Cpd 36) and(−)-9-[8-(2,2,2-Trifluoroacetyl)-8-azabicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxylicacid amide (Cpd 38)

The (+) and (−) enantiomers of compound 7f (Cpds 36 and 38), in Table 1herein were separated on a preparative chiralpak AD column (500 grams of20 micron material, 5×41 cm) using hexane/methanol/ethanol (50/25/25) aseluent, The analytes were monitored using a wavelength of 220 nm. Foranalytical work, the same column material was used (chiralpak AD, 4.6×50mm), and the same solvents, but in 80/10/10 proportion

Enant (A):-9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acidamide, Cpd 37

Using an adaptation of the method described in Procedure 5 substituting(+)-9-[8-(2,2,2-trifluoroacetyl)-8-azabicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxylicacid amide 36 for2,2,2-trifluoro-1-[3-(4-hydroxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-ethanone4a, title compound 37 was obtained as a TFA salt.

Enant (B): 9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylicacid amide, Cpd 39

Using an adaptation of the method described in Procedure 5, substituting(−)-9-[8-(2,2,2-trifluoroacetyl)-8-azabicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxylicacid amide 38 for2,2,2-trifluoro-1-[3-(4-hydroxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-ethanone4a, the title compound 39 was obtained as a TFA salt.

Example K

3-Nitro-2-phenoxy-benzoic acid, 1k

Using an adaptation of the method described in Procedure 1, substituting2-chloro-3-nitrobenzoic acid for 2-bromobenzoic acid and phenol for2-methoxyphenol, the title compound 1k was obtained.

Procedure 27

4-Nitroxanthen-9-one, 2k

A mixture of 3-nitro-2-phenoxy-benzoic acid 1k (7.1 g, 27.4 mmol) andpolyphosphoric acid (140 g) was heated to 120° C. for 4 h. The mixturewas allowed to cool to 55° C. and poured onto ice. The mixture wasstirred for t 16 h, and the solid was collected via filtration, yielding5.1 g (78.5%) of title compound 4-nitroxanthen-9-one 2k.

Procedure 28

4-Aminoxanthen-9-one, 3k

A mixture of 4-nitroxanthen-9-one 2k (4.5 g, 18.7 mmol) and 10%palladium on carbon (200 mg) in ethanol (70 mL) was hydrogenated(hydrogen pressure: 55 psi) for 16 h. The catalyst was removed viafiltration and the solvent was evaporated to yield 3.5 g (89%) of titlecompound 4-aminoxanthen-9-one 3k.

1-[3-(4-Amino-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone,4k

Using an adaptation of the method described in Procedure 4, substitutingcompound 3k for compound 3a, the title compound 4k was obtained.

Procedure 29

N-{9-[8-(2,2,2-Trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthen-4-yl}-formamide,5k

Into a flask was placed acetic anhydride (4 mL) and the reaction wascooled in an ice bath. Upon cooling, formic acid (2 mL) was added andthe mixture was heated to 50° C. for 15 min, and then cooled to rt. Uponcooling, the resulting solution (0.6 mL) was added to an ice bath-cooledsolution of compound 4k (0.300 g, 6.0 mmol) in THF (2 mL), and thereaction was heated to 50° C. for 1 h. The mixture was cooled to rt,diluted with methylene chloride, and the organic phase was washedsequentially with saturated aqueous sodium bicarbonate solution andbrine. The organic phase was dried over MgSO₄, filtered, andconcentrated to yield 0.42 g of the title compound 5k.

Procedure 30

N-[9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-yl]-formamide, Cpd44

Compound 5k (0.42g, 0.98 mmol) was added to MeOH (10 mL), and K₂CO₃ (1g) was added. The mixture was stirred for 3 h at rt. After that time,the solid was collected by vacuum filtration. The resulting filtrate wasconcentrated in vacuo. Water was added to the resulting residue and themixture was stirred for 30 min. The solid was collected by vacuumfiltration and purified by reverse phase HPLC to yield the titlecompound 44 (159 mg, 37%).

9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ylamine, Cpd 41

Using an adaptation of the methods described in Procedures 4 and 5,substituting 4-aminoxanthen-9-one 3k for 4-hydroxy-xanthen-9-one 3a inProcedure 4, the title compound 41 was obtained.

Example L

1-[3-(4-Aminoxanthen-9-ylidene)-8-azabicycio[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone,1l

Using an adaptation of the methods described in Procedure 4,substituting 4-aminoxanthen-9-one 3k for 4-hydroxy-xanthen-9-one 3a, thetitle compound 11 was obtained.

Procedure 31

[9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-yl]-pyridin-3-yl-amine,Cpd 62

To a solution of1-[3-(4-aminoxanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone1l (100 mg, 0.25 mmol) in dioxane (6 mL) was added 3-bromopyridine (0.05mL, 0.5 mmol), 1M potassium tert-butoxide in tetrahydrofuran (1.2 mL,1.2 mmol), Pd₂(dba)₃ (9 mg, 0.0125 mmol) and Xanthphos (4.5 mg, 0.0125mmol). The mixture was irradiated in a microwave reactor for 30 min at120° C. The mixture was allowed to cool to rt, water was added, and themixture was extracted with ethyl acetate. The organic phase wasseparated, dried over Na₂SO₄, filtered, and evaporated. The residue waspurified via reverse phase chromatography to yield 15 mg (12%) of titlecompound 62 as a TFA salt.

[9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-yl]-phenylamine, Cpd64

Using an adaptation of the methods described in Procedure 31,substituting bromobenzene for 3-bromopyridine, the title compound 64 wasobtained.

[9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-yl]-(4-chlorophenyl)-amine,Cpd 61

Using an adaptation of the methods described in Procedures 31, 4 and 5,substituting 4-chlorobromobenzene for 3-bromopyridine and cesiumcarbonate for potassium tert-butoxide in Procedure 30, the titlecompound 61 was obtained.

Example M

9-[8-(2,2,2-Trifluoroacetyl)-8-azabicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxylicacid methyl ester, Cpd 7

Using an adaptation of the method described in Procedure 4, substituting9-oxo-9H-xanthene-4-carboxylic acid methyl ester 4j for4-hydroxy-xanthen-9-one 3a, the title compound 7 was obtained.

Procedure 32

3-(4-Carboxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester, 1m

To a solution of compound 7 (2.2 g, 4.96 mmol) in dioxane (25 mL) wasadded a 3N sodium hydroxide solution (3.5 mL) and the mixture was heatedto reflux for 3 h. Additional 3N sodium hydroxide solution (3.5 mL) wasadded and the mixture was heated to reflux for 16 h. The mixture wasallowed to cool to rt and Boc-anhydride (3.24 g, 14.9 mmol) was added.The mixture was stirred for 24 h at rt, the solvent was evaporated, andthe residue was partitioned between water and ethyl acetate. The organicphase was separated, dried over sodium sulfate, filtered, andevaporated. The residue was used without further purification.

3-[4-(2-Dimethylaminoethylcarbamoyl)-xanthen-9-ylidene]-8-azabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester, 2m

Using an adaptation of the method described in Procedure 25,substituting3-(4-carboxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester 1m for 9-oxo-9H-xanthene-4-carboxylic acid 5j andN,N-dimethylaminoethylamine for ammonium hydroxide, the title compound2m was obtained.

Procedure 33

9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acid(2-dimethylaminoethyl)-amide, Cpd 15

Compound 2m was treated with a 95:5 mixture of trifluoroaceticacid:water at rt, and the mixture was lyophilized, yielding the titlecompound 15 as a TFA salt.

9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acidphenethyl-amide, Cpd 14

Using an adaptation of the method described in Procedures 25 and 33,substituting3-(4-carboxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester 2m for 9-oxo-9H-xanthene-4-carboxylic acid 5j and2-phenethylamine for ammonium hydroxide in Procedure 25, the titlecompound 14 was obtained.

9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic aciddimethylamide, Cpd 11

Using an adaptation of the method described in Procedures 25 and 33,substituting3-(4-carboxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester 2m for 9-oxo-9H-xanthene-4-carboxylic acid 5j anddimethylamine for ammonium hydroxide in Procedure 25, the title compound11 was obtained.

9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acidbenzylamide, Cpd 13

Using an adaptation of the method described in Procedures 25 and 33,substituting3-(4-carboxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester 2m for 9-oxo-9H-xanthene-4-carboxylic acid 5j andbenzylamine for ammonium hydroxide in Procedure 25, the title compound13 was obtained.

9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acidmethylamide, Cpd 10

Using an adaptation of the method described in Procedures 25 and 33,substituting3-(4-carboxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester 2m for 9-oxo-9H-xanthene-4-carboxylic acid 5j andmethylamine for ammonium hydroxide in Procedure 25, the title compound10 was obtained.

9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acidphenylamide, Cpd 12

Using an adaptation of the method described in Procedures 25 and 33,substituting3-(4-carboxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester 2m for 9-oxo-9H-xanthene-4-carboxylic acid 5j andaniline for ammonium hydroxide in Procedure 25, the title compound 12was obtained.

Enant (A)-9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylicacid phenylamide, Cpd 47 and Enant(B)-9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acidphenylamide, Cpd 48

The (+) and (−) enantiomers of compound 12 (Cpds 47 and 48), in Table 1herein were separated based on the following analytical chiralseparation conditions: 25 cm ADH column, eluent: 1:1acetonitrile:ethanol mixture containing 0.05% triethylamine. Cpd 47 isthe first eluting isomer, and Cpd 48 is the second eluting isomer. Cpd47: (+) ellipticity @ 246 nm; Cpd 48: (−) ellipticity @ 246 nm.

Example N

9-(8-Methyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol, Cpd 19

Using an adaptation of the method described in Procedure 4, substitutingtropinone for N-trifluoroacetyl-nortropinone, the title compound 19 wasobtained.

9-Piperidin-4-ylidene-9H-xanthen-4-ol, Cpd 16

Using an adaptation of the method described in Procedure 4, substitutingN-Boc-tropinone for N-trifluoroacetyl-nortropinone, the title compound16 was obtained.

9-(9-Methyl-9-azabicyclo[3.3.1]non-3-ylidene)-9H-xanthen-4-ol, Cpd 17

Using an adaptation of the method described in Procedure 4, substituting9-methyl-9-azabicyclo[3.3.1]nonan-3-one forN-trifluoroacetyl-nortropinone, the title compound 17 was obtained.

9-(1-Methyl-piperidin-4-ylidene)-9H-xanthen-4-ol, Cpd 18

Using an adaptation of the method described in Procedure 4, substituting1-methyl-piperidin-4-one for N-trifluoroacetyl-nortropinone, the titlecompound 18 was obtained.

9-(9-Azabicyclo[3.3.1]non-3-ylidene)-9H-xanthen-4-ol, Cpd 20

Using an adaptation of the method described in Procedure 4, substituting9-azabicyclo[3.3.1]nonan-3-one for N-trifluoroacetyl-nortropinone, thetitle compound 20 was obtained.

Enant (A):2,2,2-Trifluoro-1-[3-(4-hydroxy-xanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-ethanone,Cpd 5 and Enant (B):2,2,2-Trifluoro-1-[3-(4-hydroxy-xanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-ethanone,Cpd 6

The (+) and (−) enantiomers of2,2,2-trifluoro-1-[3-(4-hydroxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-ethanone4a (Cpds 5 and 6), in Table 1 herein were separated on a preparativechiralpak AD column (500 grams of 20 micron material, 5×41 cm) usinghexane/methanol/ethanol (50/25/25) as eluent. The analytes weremonitored using a wavelength of 220 nm. For analytical work, the samecolumn material was used (chiralpak AD, 4.6×50 mm), and the samesolvents, but in 80/10/10 proportion.

Enant (A): 9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol, Cpd 8

Using an adaptation of the method described in Procedure 5, substitutingenant (A), compound 5, for racemic2,2,2-trifluoro-1-[3-(4-hydroxy-xanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-ethanone, the title compound 8 was obtained.

Enant (B): 9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol, Cpd 9

Using an adaptation of the method described in Procedure 5, substitutingenant (B), compound 6, for racemic2,2,2-trifluoro-1-[3-(4-hydroxy-xanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-ethanone,the title compound 9 was obtained.

Enant (A)-9-(8-Benzyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol,Cpd 45 and Enant(B)-9-(8-Benzyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol, Cpd46

The (+) and (−) enantiomers of9-(8-benzyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol 32 (Cpds45 and 46), in Table 1 herein were separated based on the followinganalytical chiral separation conditions: 25 cm ADH column, eluent:ethanol containing 0.05% triethylamine. Cpd 45 is the first elutingisomer, and Cpd 46 is the second eluting isomer.

Enant(A)-9-(8-Pyridin-3-ylmethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol,Cpd 49 and Enant(B)-9-(8-Pyridin-3-ylmethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol,Cpd 50

The (+) and (−) enantiomers of9-(8-pyridin-3-ylmethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol31 (Cpds 49 and 50), in Table 1 herein were separated based on thefollowing analytical chiral separation conditions: 15 cm ASH column,eluent: ethanol containing 0.05% triethylamine. Cpd 49 is the firsteluting isomer, and Cpd 50 is the second eluting isomer. Cpd 49: (−)ellipticity @ 284 nm; Cpd 50: (+) ellipticity @ 284 nm.

Enant (A)-9-(8-Methyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol,Cpd 51 and Enant(B)-9-(8-Methyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol, Cpd52

The (+) and (−) enantiomers of9-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol 19 (Cpds51 and 52), in Table 1 herein were separated based on the followinganalytical chiral separation conditions: 25 cm ADH column, eluent:ethanol containing 0.05% triethylamine. Cpd 51 is the first elutingisomer, and Cpd 52 is the second eluting isomer. Cpd 51: (+) ellipticity@ 284 nm; Cpd 52: (−) ellipticity @ 284 nm.

Enant(A)-9-(8-Furan-3-ylmethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol,Cpd 58 and Enant(B)-9-(8-Furan-3-ylmethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol,Cpd 57

The (+) and (−) enantiomers of9-(8-furan-3-ylmethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol25 (Cpds 57 and 58), in Table 1 herein were separated based on thefollowing analytical chiral separation conditions: 25 cm ADH column,eluent: ethanol containing 0.05% triethylamine. Cpd 57 is the firsteluting isomer, and Cpd 58 is the second eluting isomer. Cpd 57: (+)ellipticity @ 284 nm: Cpd 58: (−) ellipticity @ 284 nm.

Enant(A)-9-(8-Pyridin-2-ylmethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol,Cpd 59 and Enant(B)-9-(8-Pyridin-2-ylmethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol,Cpd 60

The (+) and (−) enantiomers of9-(8-pyridin-2-ylmethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthen-4-ol21 (Cpds 59 and 60), in Table xxx herein were separated based on thefollowing analytical chiral separation conditions: 15 cm ADH column,eluent: isopropanol containing 0.05% triethylamine. Cpd 59 is the firsteluting isomer, and Cpd 60 is the second eluting isomer. Cpd 59: (−)ellipticity @ 284 nm; Cpd 60: (+) ellipticity @ 284 nm.

Example P Enant(A)-9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acidphenethylamide, Cpd 55 and Enant(B)-9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acidphenethylamide, Cpd 56

The (+) and (−) enantiomers of compound 14 (Cpds 55 and 56), in Table 1herein were separated based on the following analytical chiralseparation conditions: 15 cm ASH column, eluent: methanol containing0.05% triethylamine. Cpd 55 is the first eluting isomer, and Cpd 56 isthe second eluting isomer. Cpd 55: (+) ellipticity @ 263 nm; Cpd 56: (−)ellipticity @ 263 nm.

Enant (A)-9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylicacid benzylamide, Cpd 53 and Enant(B)-9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-4-carboxylic acidbenzylamide, Cpd 54

The (+) and (−) enantiomers of compound 13 (Cpds 53 and 54), in Table 1herein were separated based on the following analytical chiralseparation conditions: 15 cm ASH column, eluent: methanol containing0.05% triethylamine. Cpd 53 is the first eluting isomer, and Cpd 54 isthe second eluting isomer. Cpd 53: (+) ellipticity @ 258 nm; Cpd 54: (−)ellipticity @ 258 nm.

Example Q

1-[3-(4-Bromoxanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone,1q

Using an adaptation of the method described in Procedure 4, substituting4-bromoxanthen-9-one 3j for 4-hydroxy-xanthen-9-one 3a, the titlecompound 1q was obtained.

Enant(A)-1-[3-(4-Bromoxanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone,2q and Enant(B)-1-[3-(4-Bromoxanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone,3q

The (+) and (−) enantiomers of compound 1q (Cpds 2q and 3q) wereseparated on a preparative chiralpak AD column (500 grams of 20 micronmaterial, 5×41 cm) using hexane/methanol/ethanol (50/25/25) as eluent.The analytes were monitored using a wavelength of 220 nm. For analyticalwork, the same column material was used (chiralpak AD, 4.6×50 mm), andthe same solvents, but in 80/10/10 proportion.

Enant (A)-3-(4-Bromo-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane, 4q

Using an adaptation of the method described in Procedure 5, substitutingenant(A)-1-[3-(4-bromoxanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone2q for2,2,2-trifluoro-1-[3-(4-hydroxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-ethanone4a, a 3N sodium hydroxide solution for potassium carbonate, and applyingreflux temperatures in stead of rt, the title compound 4q was obtained.

Enant(A)-3-(4-Bromo-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester, 5q

Using an adaptation of the method described in Procedure 32,substituting enant(A)-3-(4-bromo-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane 4q for Cpd7, the title compound 5q was obtained.

Procedure 34

Enant(A)-3-(4-Cyano-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester, 6q

To a solution of enant(A)-3-(4-bromo-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester 5q (3 g, 6.6 mmol) in dimethyl formamide (90 mL)were added copper cyanide (3 g, 33 mmol) and palladium tetrakistriphenylphosphine dichloride (45 mg, 0.66 mmol). The mixture was heatedto 140° C. for 16 h. The mixture was allowed to cool to rt and water wasadded. The mixture was extracted with methylene chloride. The organiclayer was separated, dried, filtered, and evaporated. The residue waspurified via flash column chromatography to yield title compound 6q.

Procedure 35

Enant(A)-9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-N-hydroxy-9H-xanthene-4-carboxamidine,Cpd 42

To a solution of enant(A)-3-(4-cyano-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester 6q (0.3 g, 0.72 mmol) in ethanol (8 mL) were addedhydroxylamine hydrochloride (0.15 g, 2.2 mmol) and potassium carbonate(0.2 g, 1.4 mmol). The mixture was heated to reflux for 16 h. Themixture was allowed to cool to rt and the solids were removed viafiltration, The filtrate was evaporated and the residue was dissolved inmethylene chloride containing 10% trifluoroacetic acid. The mixture wasstirred for 1 h at rt and evaporated. The residue was purifiede viareverse phase HPLC, yielding 128 mg (58%) of title compound 42 as a TFAsalt; (+) ellipticity @ 269 nm.

Enant(B)-9-(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-N-hydroxy-9H-xanthene-4-carboxamidine,Cpd 43

Using an adaptation of the method described in Procedures 5, 22 and 24,substituting Cpd 3q for2,2,2-trifluoro-1-[3-(4-hydroxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-ethanone4a, a 3N sodium hydroxide solution for potassium carbonate, and applyingreflux temperatures in stead of rt, in Procedure 5, the title compound43 was obtained as a TFA salt; (−) ellipticity @ 269 nm.

Example R

9-Oxo-9H-thioxanthene-4-carboxylic acid, 1r

A sample of 2-(2-cyanophenylsulfanyl)-benzoic acid (15 g, 58.8 mmol) washeated in polyphosphoric acid (300 g) at 170° C. for 16 h. The mixturewas allowed to cool to rt and poured onto ice. The precipitate wascollected via filtration, yielding 15 g (quant.) of title compound 1r.The material was used without further purification.

9-Oxo-9H-thioxanthene-4-carboxylic acid amide, 2r

A sample of 9-oxo-9H-thioxanthene-4-carboxylic acid 1r (15 g, 58.7 mmol)was heated in sulfonyl chloride (70 mL) for 2 h. Excess sulfonylchloride was removed via evaporation. The residue was dissolved intetrahydrofuran (200 mL), and triethylamine (16.4 mL, 117.4 mmol) and a0.5 M solution of ammonia in dioxane (176 mL, 88.5 mmol) were added.Methanol (20 mL) was added, and the mixture was evaporated. Water andchloroform were added, and a precipitate formed. The precipitate wasisolated via filtration, and yielded 3.5 g (25%) of title compound 2r.The organic layer was separated, dried, filtered, and evaporated toyield 11 g of recovered 1r.

9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-thioxanthene-4-carboxylic acidamide, Cpd 63

Using an adaptation of the method described in Procedure 4, substituting9-oxo-9H-thioxanthene-4-carboxylic acid amide 2r for4-hydroxy-xanthen-9-one 3a and N-Boc-nortropinone forN-trifluoroacetyl-nortropinone, the title compound 63 was obtained.

Compounds 1 through 64 of Formula (I), in Table 1 were preparedaccording to the methods described by the Schemes and Examples, herein.

TABLE 1 Structural and Mass Spectral Data MS Parent Cpd Peak MS No. R₁ AR₂ Y Obs'd Calc'd  1 methoxy —(CH₂)₂— H O 320.0 319.4  2 hydroxy—(CH₂)₂— H O 306.1 305.4  3 aminocarbonyl —(CH₂)₂— H O 333.2 332.4  4aminocarbonyl —(CH₂)₂— furan-2-yl O 413.2 412.5 methyl 5- hydroxy—(CH₂)₂— trifluoromethyl O 402.0 401.4 Enant. A carbonyl 6- hydroxy—(CH₂)₂— trifluoromethyl O 401.9 401.4 Enant. B carbonyl  7 methoxy—(CH₂)₂— trifluoromethyl O 444.1 443.4 carbonyl carbonyl 8- hydroxy—(CH₂)₂— H O 306.0 305.4 Enant. A 9- hydroxy —(CH₂)₂— H O 306.0 305.4Enant. B 10 methylamino —(CH₂)₂— H O 347.0 346.4 carbonyl 11dimethylamino —(CH₂)₂— H O 360.9 360.5 carbonyl 12 phenylaminocarbonyl—(CH₂)₂— H O 408.9 408.5 13 phenylmethylaminocarbonyl —(CH₂)₂— H O 422.9422.5 14 phenylethyl- —(CH₂)₂— H O 437.0 436.6 aminocarbonyl 15(2-dimethyl —(CH₂)₂— H O 404.18 403.5 amino-ethyl) aminocarbonyl 16hydroxy absent H O 280.1 279.3 17 hydroxy —(CH₂)₃— methyl O 334.2 333.418 hydroxy absent methyl O 294.1 293.4 19 hydroxy —(CH₂)₂— methyl O320.1 319.4 20 hydroxy —(CH₂)₃— H O 320.1 319.4 21 hydroxy —(CH₂)₂—pyridin-2-yl O 397.2 396.5 methyl 22 hydroxy —(CH₂)₂— pyridin-4-yl O397.2 396.5 methyl 23 hydroxy —(CH₂)₂— 2-hydroxy- O 413.2 412.5pyridin-4-yl methyl 24 hydroxy —(CH₂)₂— thien-2-yl O 402.1 401.5 methyl25 hydroxy —(CH₂)₂— furan-3-yl O 386.2 385.5 methyl 26 hydroxy —(CH₂)₂—cyclopropyl O 360.2 359.5 methyl 27 hydroxy —(CH₂)₂— 2-methyl- O 374.2373.5 but-2-enyl 28 hydroxy —(CH₂)₂— 2-phenyl- O 462.2 461.6imidazol-4-yl methyl 29 aminocarbonyl —(CH₂)₂— trifluoromethyl O 429.1428.41 carbonyl 30 hydroxy —(CH₂)₂— phenethyl O 410.2 409.53 31 hydroxy—(CH₂)₂— pyridin-2- O 397.2 396.49 ylmethyl 32 hydroxy —(CH₂)₂—phenylmethyl O 396.2 395.50 33 hydroxy —(CH₂)₂— benzothien-3- O 452.2451.59 ylmethyl 34 hydroxy —(CH₂)₂— 1H-imidazol-2- O 386.2 385.47ylmethyl 35 hydroxy —(CH₂)₂— isoquinolin-5- O 447.2 446.55 ylmethyl 36aminocarbonyl —(CH₂)₂— trifluoromethyl O 429.2 428.41 carbonyl 37aminocarbonyl —(CH₂)₂— H O 333.2 332.40 38 aminocarbonyl —(CH₂)₂—trifluoromethtyl O 429.2 428.41 carbonyl 39 aminocarbonyl —(CH₂)₂— H O333.2 332.40 40 aminocarbonyl —(CH₂)₂— trifluoromethyl S 444.47 carbonyl41 amino —(CH₂)₂— H O 305.2 304.39 42 hydroxyamidino —(CH₂)₂— H O 348.2347.42 Enant. A 43 hydroxyamidino —(CH₂)₂— H O 348.2 347.42 Enant. B 44formylamino —(CH₂)₂— H O 333.2 332.40 45 hydroxy —(CH₂)₂— phenylmethyl O396.1 395.50 46 phenylaminocarbonyl —(CH₂)₂— H O 396.1 395.50 47phenylaminocarbonyl —(CH₂)₂— H O 409.2 408.50 48 hydroxy —(CH₂)₂—pyridin-3- O 409.2 408.50 ylmethyl 49 hydroxy —(CH₂)₂— pyridin-3- O397.2 396.49 ylmethyl 50 hydroxy —(CH₂)₂— methyl O 397.2 396.49 51hydroxy —(CH₂)₂— methyl O 320.2 319.40 52 pyridin-2-yloxy —(CH₂)₂— H O320.2 319.40 53 phenylmethylamioncarbonyl —(CH₂)₂— H O 423.2 422.53 54phenethyl —(CH₂)₂— H O 423.2 422.53 aminocarbonyl 55 phenethyl —(CH₂)₂—H O 437.2 436.55 aminocarbonyl 56 hydroxy —(CH₂)₂— furan-3- O 437.2436.55 ylmethyl 57 hydroxy —(CH₂)₂— furan-3- O 386.1 385.46 ylmethyl 58hydroxy —(CH₂)₂— pyridin-2- O 386.1 385.46 ylmethyl 59 hydroxy —(CH₂)₂—pyridin-2-ylmethyl O 397.2 396.49 60 hydroxy —(CH₂)₂— pyridin-2-ylmethylO 397.2 396.49 61 4-chloro- —(CH₂)₂— H O 383.1 382.46 phenylamino 62pyridin-3-yl —(CH₂)₂— H O 415.2 414.94 amino 63 aminocarbonyl —(CH₂)₂— HS 382.3 381.48 64 phenylamino —(CH₂)₂— H O 348.47

Biological Examples Example 1 Rat Brain Delta Opioid Receptor BindingAssay

Procedure: Male, Wistar rats (150-250 g, VAF, Charles River, Kingston,N.Y) were killed by CO₂, and their brains removed and placed immediatelyin ice cole Tris HCl buffer (50 mM, pH 7.4). The forebrains wereseparated from the remainder of the brain by a coronal transection,beginning dorsally at the colliculi and passing ventrally through themidbrain-pontine junction. After dissection, the forebrains werehomogenized in Tris buffer in a Teflon®-glass homogenizer. Thehomogenate was diluted to a concentration of 1 g of forebrain tissue per80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet wasresuspended in the same volume of Tris buffer containing 5 mM MgCl₂ withseveral brief pulses from a Polytron homogenizer. This particulatepreparation was used for the delta opioid binding assays. Followingincubation with the delta selective peptide ligand ˜4 nM [³H]DPDPE or0.15 nM [³H]naltrindole at 25° C. for 2.5 h in a 96-well plate withtotal volume of 1 mL, the plate contents were filtered through Wallacfiltermat B sheets on a Tomtec 96-well harvester. The filters wererinsed three times with 2 mL of 10 mM HEPES (pH 7.4), and dried in a 650W microwave oven for 1.75 min twice. To each sample area 2×50 μL ofBetaplate Scint scintillation fluid (LKB) was added and theradioactivity quantified on a LKB (Wallac) 1205 BetaPlate liquidscintillation counter.

Analysis: The data from the scintillation counter were used to calculateeither the % inhibition compared to control binding (when only a singleconcentration of test compound was evaluated) or a K_(i) value (when arange of concentrations was tested). Percent inhibition was calculatedas: [(total dpm-test compound dpm)/(total dpm-nonspecific dpm)]*100. Kdand Ki values were calculated using GraphPad PRISM data analysisprogram. Resultant data is shown in Table 1.

Example 2 Rat Brain Mu Opioid Receptor Binding Assay

Procedure: Male, Wistar rats (150-250 g, VAF, Charles River, Kingston,N.Y.) were killed by CO₂, and their brains removed and placedimmediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrainswere separated from the remainder of the brain by a coronal transection,beginning dorsally at the colliculi and passing ventrally through themidbrain-pontine junction. After dissection, the forebrains werehomogenized in Tris buffer in a Teflon®-glass homogenizer. Thehomogenate was diluted to a concentration of 1 g of forebrain tissue per80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet wasresuspended in the same volume of Tris buffer containing 5 mM MgCl₂ withseveral brief pulses from a Polytron homogenizer. This particulatepreparation was used for the delta opioid binding assays. Followingincubation with the mu selective peptide ligand, ˜0.8 nM [³H]DAMGO, at25° C. for 2.5 h in a 96-well plate with total assay volume of 1 mL, theplate contents were filtered through Wallac filtermat B sheets on aTomtec 96-well harvester. The filters were rinsed three times with 2 mLof 10 mM HEPES (pH 7.4), and dried in a 650 W microwave oven for 1.75min twice. To each sample area 2×40 μL of Betaplate Scint scintillationfluid (LKB) was added and the radioactivity quantifed on a LKB (Wallac)1205 BetaPlate liquid scintillation counter. Analysis: The data from thescintillation counter were used to calculate either the % inhibitioncompared to control binding (when only a single concentration of testcompound was evaluated) or a K_(i) value (when a range of concentrationstested). Percent inhibition was calculated as: [(total dpm-test compounddpm)/(total dpm-nonspecific dpm)]*100. Kd and Ki values were calculatedusing GraphPad PRISM data analysis program. Resultant data is shown inTable 1.

Example 3 Functional Assay: [³⁵S]GTPγS Binding Assay in NG108-15 CellMembranes (delta opioid)

Methods: NG108-15 cell membranes were purchased from Applied CellSciences (Rockville, Md.). A sample (8 mg/mL) of membrane proteinsuspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose. Membraneswere maintained at 4-8° C. A 1 mL volume of membranes was added into 10mL cold binding assay buffer. The assay buffer contained 50 mM Tris, pH7.6, 5 mM MgCl₂, 100 mM NaCl, 1 mM DTT and 1 mM EGTA. The membranesuspension was homogenized twice with a Polytron, and centrifuged at3000 rpm for 10 min. The supernatant was then centrifuged at 18,000 rpmfor 20 min. Ten mL assay buffer was added into the pellet containingtube. The pellet and buffer were mixed with a Polytron.

Incubation procedure: The pellet membranes (75 μg/mL) were preincubatedwith SPA (10 mg/mL) at 25° C. for 45 min in the assay buffer. The SPA (5mg/mL) coupled with membranes (37.5 μg/mL) was then incubated with 0.1nM [³⁵S] GTPγS in the same Tris buffer containing 100 μM GDP in totalvolume of 200 μL. Increasing concentrations of receptor agonists wereused to stimulate [³⁵S]-GTPγS binding. The basal binding was tested inthe absence of agonists and non-specific binding was tested in thepresence of 10 μM unlabeled GTPγS. The data were analyzed on a PackardTop Count.

DATA% of Basal=(stimulated−non specific)*100/(basal−non specific).EC₅₀ values were calculated using GraphPad Prism. Resultant data isshown in Table 1.

Example 4 Functional Assay: [³⁵S]GTPγS Binding Assays in CHO-hMOR CellMembranes

Methods: CHO-hMOR cell membranes were purchased from Receptor Biology,Inc. (Baltimore, Md.). About 10 mg/mL of membrane protein was suspendedin 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose, and the suspensionkept on ice. A 1 mL volume of membranes was added to 15 mL cold bindingassay buffer containing 50 mM HEPES, pH 7.6, 5 mM MgCl₂, 100 mM NaCl, 1mM DTT and 1 mM EDTA. The membrane suspension was homogenized with aPolytron and centrifuged at 3,000 rpm for 10 min. The supernatant wasthen centrifuged at 18,000 rpm for 20 min. The pellet was resuspended in10 mL assay buffer with a Polytron. The membranes were preincubated withwheat germ agglutinin coated SPA beads (Amersham) at 25° C. for 45 minin the assay buffer. The SPA bead (5 mg/mL) coupled membranes (10 μg/mL)were then incubated with 0.5 nM [³⁵S]GTPγS in the assay buffer. Thebasal binding was that taking place in the absence of added testcompound; this unmodulated binding was considered as 100%, with agoniststimulated binding rising to levels significantly above this value. Arange of concentrations of receptor agonist was used to stimulate[³⁵S]GTPγS binding. Both basal and non-specific binding was tested inthe absence of agonist; non-specific binding determination included 10μM unlabeled GTPγS.

Compounds were tested for function as antagonists by evaluating theirpotential to inhibit agonist-stimulated GTPγS binding. Radioactivity wasquantified on a Packard TopCount. The following parameters werecalculated:

${\%\mspace{11mu}{stimulation}} = {\frac{( {{{test}\mspace{14mu}{compound}\mspace{14mu}{cpm}} - {{non}\text{-}{specific}\mspace{14mu}{cpm}}} )}{( {{{basal}\mspace{14mu}{cpm}} - {{non}\text{-}{specific}\mspace{14mu}{cpm}}} )} \times 100.}$${\%\mspace{11mu}{inhibition}} = {\frac{( {{\%\mspace{11mu}{stimulation}\mspace{14mu}{by}\mspace{14mu} 1\mspace{11mu}{µM}\mspace{14mu}{DAMGO}} - {\%\mspace{11mu}{stimulation}\mspace{14mu}{by}\mspace{14mu}{test}\mspace{14mu}{compound}}} )}{( {{\%\mspace{11mu}{stimulation}\mspace{14mu}{by}\mspace{14mu} 1\mspace{11mu}{µM}\mspace{14mu}{DAMGO}} - 100} )} \times 100}$EC₅₀ values were calculated using GraphPad Prism. Resultant data isshown in Table 1.

TABLE 1 Biological Data Functional Data delta GTPγS Binding Data bindingmu GTPγS rMOR EC50 binding Cpd rDOR (Ki, (nM)/Rel EC50 No. (Ki, nM) nM)Eff (nM)/Rel Eff  1* 3802 1794 — —  2 0.48 7.0 50.9 382   (0.67) (0.37) 3 3.2 29.4 42.0 3964  4 2.3 2.5 9.40 4043  5 2112 5621  6 8496 >10000 7 >10000 >10000  8 0.56 3.5 9.98 902  9 68.2 63.6 10 1573, 136 27, 51.0617 >10,000 11 3109 471 12 272, 67.9 32 30.3 611 (1.03) (0.96) 13 216,17.8 15, 12.7 5.68 717 (0.87) (0.67) 14 864, 58.3 44, 36.2 10.4 997(0.92) (0.54) 15 1420 336 16 15.1 776 964 17 132 221 18 330 4612 19 28.3372 768 >10,000 20 20.2 32.6 180 7080 21 0.007 0.10 21.8 >10,000 22 0.97358 2716 >10,000 23 1.50 2.18 52.8 12365 24 0.046 1.58 6.05 >10,000 250.26 0.56 1.08 2815 26 5.43 65.9 194 >10,000 27 0.35 2.03 9.80 >10,00028 192 58.5 1378 >10,000 30 63.5 27.7 2964 >10,000 31 0.028 1.23 1348090 32 0.023 0.29 28.6 >10,000 33 137 168 34 0.028 0.53 3.33 1610 35180 286 36 1793 >10,000 37 4.00 29.0 156 878 38 6440 >10,000 39 31.996.4 1243 42 237 56.5 43 >10,000 >10,000 44 19.2 45.2 7.03 45 9.62 11.371419.8 46 0.03 0.19 10.2 47 250.45 292.95 48 3.71 3.58 101.1 49 62.61443.20 50 0.08 0.68 217.9 51 11.2 138.1 59.2 52 323.4 1323 53 1128 202755 100.4 200 56 49.6 6.96 40.1 57 246 36.5 58 0.1 0.45 2.6 59 0.07 0.3960 0.01 0.01 61 395 3156 62 107.5 158.8 63 0.71 3.31 2.7 64 862 2419 *aprodrug form rDOR Ki: Rat delta opioid receptor binding constant rMORKi: Rat mu opioid receptor binding constant

Example 5 Rat CFA Radiant Heat Model of Inflammatory Pain

Intraplantar injection of Complete Freund's Adjuvant (CFA) in rodentsresults in a strong, long-lasting inflammatory reaction, characterizedby a chronic and pronounced hyperalgesia to both thermal and mechanicalstimuli. These effects peak between 24-72 h following injection, and canlast for several days to few few weeks. To assess the ability ofcompounds to reverse thermal hyperalgesia, male Sprague-Dawley rats(200-350 g) are given an intraplantar injection of CFA (1:1 CFA:saline,100 μL) into their left hindpaw. Following a 24-h incubation period,response latencies on the Radiant Heat Paw Stimulator (RH) are obtainedand compared to baseline (pre-CFA) latencies. The RH deviceautomatically registers lifting of the paw from the surface of theglass. Only rats that exhibit at least a 25% reduction in responselatency from baseline (i.e. hyperalgesia) are included in furtheranalysis. Following the post CFA latency assessment, rats are dosedorally (2.5 mL/kg) with test compound or vehicle(hydroxypropylmethylcellulose, HPMC). Percent reversal of hyperalgesiais calculated for each animal as (Treatment Response−postCFAResponse)/(preCFA Response−postCFA Response)×100. Therefore, a return tonormal pre-CFA thresholds is defined as 100% efficacy, whereas no changefrom post-CFA thresholds is 0% efficacy. Average % reversal ofhyperalgesia is then calculated for each treatment group (n=6-8rats/group).

Example 6

The therapeutic effect of delta opioid agonists has been demonstratedin:

Pain

-   (Fang, (1995) Shengli Kexue Jinzhan 26:137-40; Garzon, (1995)    Analgesia (Elmsford, N.Y.) 1:131-44; Mafthes, Maldonado, Simonin,    Valverde, Slowe, Kitchen, Befort, Dierich, Le Meur and et    al., (1996) Nature (London) 383:819-823; Stevens, (1996) Journal of    Pharmacology and Experimental Therapeutics 276:440-8; Dondio,    Ronzoni and Petrillo, (1997) Expert Opinion on Therapeutic Patents    7:1075-1098; Hutcheson, Sanchez-Blazquez, Rodriguez-Diaz, Garzon,    Schmidhammer, Borsodi, Roques and Maldonado, (1999) European Journal    of Pharmacology 383:29-37; Fraser, Pradhan, Clarke and    Wahlestedt, (2000) Journal of Pharmacology and Experimental    Therapeutics 295:1135-1141; Scheideler, (2000) Current Opinion in    Central & Peripheral Nervous System Investigational Drugs 2:171-177;    Wei, Brown, Takasaki, Plobeck, Delorme, Zhou, Yang, Jones, Gawell,    Gagnon, Schmidt, Yue, Walpole, Payza, St-Onge, Labarre, Godbout,    Jakob, Butterworth, Kamassah, Morin, Projean, Ducharme and    Roberts, (2000) Journal of Medicinal Chemistry 43:3895-3905; Nagase,    Yajima, Fujii, Kawamura, Narita, Kamei and Suzuki, (2001) Life    Sciences 68:2227-2231; Abeyta, Dettmer, Barnes, Vega, Carta,    Gallegos, Raymond-Stintz, Savage, Valenzuela and Saland, (2002)    Brain Research 931:100-5. FIELD Reference Number: FIELD Journal    Code:0045503 FIELD Call Number:; Cahill, Morinville, Hoffert,    O'Donnell and Beaudet, (2003) Pain 101:199-208; Collina, Azzolina,    Vercesi, Brusotti, Rossi, Barbieri, Lanza, Mennuni, Alcaro,    Battaglia, Linati and Ghislandi, (2003) Farmaco 58:939-946; Hurley,    Banfor and Hammond, (2003) Neuroscience (Oxford, United Kingdom)    118.789-796).    Inflammatory Pain States-   (Stein, Millan, Shippenberg, Peter and Herz, (1989) Journal of    Pharmacology and Experimental Therapeutics 248:1269-75; Antonijevic,    Mousa, Schaefer and Stein, (1995) Journal of Neuroscience 15:165-72;    Ballet, Mauborgne, Benoliel, Bourgoin, Hamon, Cesselin and    Collin, (1998) Brain Research 796:198-208; Hurley and    Hammond, (2001) Journal of Neuroscience 21:2536-2545; Przewlocki and    Przewlocka, (2001) European Journal of Pharmacology 429:79-91;    Spetea, Rydelius, Nylander, Ahmed, Bileviciute-Ljungar, Lundeberg,    Svensson and Kreicbergs, (2002) European Journal of Pharmacology    435:245-252; Bao, Jin, Zhang, Wang, Xu, Zhang, Wang, Ning, Cai,    Guan, Xiao, Xu, He, Hokfelt, Zhou and Zhang, (2003) Neuron    37:121-133; Cahill, Morinville, Hoffert, O'Donnell and    Beaudet, (2003) Pain 101:199-208; Martin, Matifas, Maldonado and    Kieffer Brigitte, (2003) European Journal of Neuroscience 17:701-8.    FIELD Reference Number: FIELD Journal Code:8918110 FIELD Call    Number:; Petrillo, Angelici, Bingham, Ficalora, Garnier, Zaratin,    Petrone, Pozzi, Sbacchi, Stean, Upton, Dondio and Scheideler, (2003)    Journal of Pharmacology and Experimental Therapeutics    307:1079-1089).    Visceral Pain-   (Schmauss and Yaksh, (1984) Journal of Pharmacology and Experimental    Therapeutics 228:1-12; Craft, henley, Haaseth, Hruby and    Porreca, (1995) Journal of Pharmacology and Experimental    Therapeutics 275:1535-42; Su, Wachtel and Gebhart, (1998) Journal of    Neurophysiology 80:3112-3119; Gebhart, Su, Joshi, Ozaki and    Sengupta, (1999) Progress in Pain Research and Management    14:225-235; Sora, Li, Funada, Kinsey and Uhl, (1999) European    Journal of Pharmacology 366:R3-R5; Gebhart, (2000) Regional    Anesthesia and Pain Medicine 25:632-638; Martin, Matifas, Maldonado    and Kieffer Brigitte, (2003) European Journal of Neuroscience    17:701-8).    Lung-   (Kuo, Rohde, Barnes and Rogers, (1992) British Journal of    Pharmacology 105:361-6; Campa, Schreiber, Bepler, Bishop, McNutt,    Chang and Patz, (1996) Cancer Research 56:1695-701; Bolli, Shinmura,    Tang, Kodani, Xuan, Guo and Dawn, (2002) Cardiovascular Research    55:506-519; Janssens, Leenaerts, Fernandez-Gadea, Gomez-Sanchez,    Flameng, Herijgers, Meert and Borgers, (2003) PCT Int. AppI. 75 pp.;    McLeod, Tulshian and Hey, (2003) Expert Opinion on Therapeutic    Patents 13:1501-1512).    Cardioprotection-   (Schultz, Hsu, Nagase and Gross, (1998) American Journal of    Physiology 274:H909-H914; Fryer, Hsu, Eells, Nagase and    Gross, (1999) Circulation Research 84:846-851; Fryer, Hsu, Nagase    and Gross, (2000) Journal of Pharmacology and Experimental    Therapeutics 294:451-457; Fryer, Hsu and Gross, (2001) Basic    Research in Cardiology 96:136-142; Fryer, Patel, Hsu and    Gross, (2001) American Journal of Physiology 281:H1184-H1192; Fryer,    Pratt, Hsu and Gross, (2001) Journal of Pharmacology and    Experimental Therapeutics 296:642-649; Fryer, Wang, Hsu and    Gross, (2001) American Journal of Physiology 280:H1346-H1353; Fryer,    Wang, Hsu, Nagase and Gross, (2001) Journal of Pharmacology and    Experimental Therapeutics 299:477-482; Huh, Gross, Nagase and    Liang, (2001) American Journal of Physiology 280:H377-H383; Karck,    Tanaka, Bolling, Simon, Su, Oeltgen and Haverich, (2001) Journal of    Thoracic and Cardiovascular Surgery 122:986-992; McPherson and    Yao, (2001) Anesthesiology 94:1082-1088; Patel, Hsu, Moore and    Gross, (2001) Journal of Molecular and Cellular Cardiology    33:1455-1465; Rebrova, Maslov and Tam, (2001) Voprosy Meditsinskoi    Khimii 47:338-345; Patel, Ludwig, Fryer, Hsu, Warltier and    Gross, (2002) FASEB Journal 16:1468-1470, 10.1096/fj.02-0170fje;    Sigg, Coles, Oeltgen and laizzo, (2002) American Journal of    Physiology 282:H1953-H1960; Zhang, McPherson, Liu, Baman, McPherson,    Rock and Yao, (2002) Journal of Pharmacology and Experimental    Therapeutics 301:1012-1019; Patel, Hsu and Gross, (2004) Basic    Research in Cardiology 99:38-45; Patel, Hsu and Gross, (2004) Life    Sciences 75:129-140; Pear and Gross, (2004) Basic research in    cardiology 99:29-37. FIELD Reference Number: FIELD Journal    Code:0360342 FIELD Call Number; Shinmura, Nagai, Tamaki and    Bolli, (2004) Basic research in cardiology 99:46-55.    Urinary Dysfunction-   (Dray and Metsch, (1984) Neuroscience Letters 47:81-4; Dray, (1985)    Journal of Pharmacological Methods 13:157-65; Craft, henley,    Haaseth, Hruby and Porreca, (1995) Journal of Pharmacology and    Experimental Therapeutics 275:1535-42; Murase, Hamada and    Asaki, (1996) PCT Int. Appl. 93 pp.; Su, Sengupta and    Gebhart, (1997) Journal of Neurophysiology 77:1566-1580; Sezen,    Kenigs and Kapusta, (1998) Journal of Pharmacology and Experimental    Therapeutics 287:238-245; Chang, Gengo, Biciunas, Ma, Pendergast and    Jan, (2003) PCT Int. Appl 73 pp.; Igari, Yanai and Goya, (2004) PCT    Int. Appl. 30 pp.).    Cough-   (Kamei, Iwamoto, Suzuki, Nagase, Misawa and Kasuya, (1993) European    Journal of Pharmacology 234:117-20; Kotzer, Hay, Dondio, Giardina,    Petrillo and Underwood, (2000) Journal of Pharmacology and    Experimental Therapeutics 292:803-9; McLeod, Tulshian and    Hey, (2003) Expert Opinion on Therapeutic Patents 13:1501-1512).    Anxiety-   (Roberts, Gold, Polis, McDonald, Filliol, Kieffer and Koob, (2001)    Alcoholism: Clinical and Experimental Research 25:1249-1256;    Gaveriaux-Ruff and Kieffer, (2002) Neuropeptides (Edinburgh, United    Kingdom) 36:62-71; Masuda, Suzuki, Takemura, Sugawara, Guo, Liu,    Kawarada, Shimizu and Sugiyama, (2003) Tohoku Journal of    Experimental Medicine 201:23-27; Noble and Roques, (2003) Drugs of    Today 39:897-908).    Depression-   (Broom, Jutkiewicz, Folk, Traynor, Rice and Woods, (2002)    Psychopharmacology (Berlin, Germany) 164:42-48; Broom, Jutkiewicz,    Folk, Traynor, Rice and Woods, (2002) Neuropsychopharmacology    26:744-755; Broom, Jutkiewicz, Rice, Traynor and Woods, (2002)    Japanese Journal of Pharmacology 90:1-6; Varona, Gil, Saracibar,    Maza, Echevarria and Irazusta, (2003) Arzneimittel-Forschung    53.21-25).    Parkinsons Disease-   (Barneoud, Descombris, Aubin and Abrous, (2000) European journal of    neuroscience 12:322-36. Hill, Hille and Brotchie, (2000) Drug News &    Perspectives 13:261-268; Hudzik, Howell, Payza and Cross, (2000)    European Journal of Pharmacology 396:101-107; Hille, Fox, Maneuf,    Crossman and Brotchie, (2001) Experimental Neurology 172:189-198).

Example 7

The therapeutic effect of mu opioid agonists has been demonstrated in:

Pain

-   (Pasternak, (1986) Advances in Pain Research and Therapy 8:337-44;    Garzon and Sanchez-Blazques, (1995) Life Sciences 56:PL237-PL242;    Matthes, Maldonado, Simonin, Valverde, Slowe, Kitchen, Befort,    Dierich, Le Meur and et al., (1996) Nature (London) 383:819-823;    Stevens, (1996) Journal of Pharmacology and Experimental    Therapeutics 276:440-8; Dayer, Desmeules and Collart, (1997) Drugs    53:18-24; Valverde, Maldonado and Kieffer, (1998) CNS Drugs 10:1-10;    Kharkevich and Churukanov, (1999) European Journal of Pharmacology    375:121-131; Pasternak, (2000) Progress in Pain Research and    Management 16:147-162; Gutstein and Akil, J. G. Hardman and L. E.    Limbird (2001) The pharmacological basis of therapeutics 569-619;    Pasternak, (2001) Neuroscientist 7:220-231; Smith, Ross, Nielsen and    Saini, (2001) European Journal of Pain (London, United Kingdom)    5:135-136; Wells, Bartlett, Ananthan and Bilsky, (2001) Journal of    Pharmacology and Experimental Therapeutics 297:597-605; Abbadie and    Pasternak, (2003) Handbook of Chemical Neuroanatomy 20:1-29;    Collina, Azzolina, Vercesi, Brusotti, Rossi, Barbieri, Lanza,    Mennuni, Alcaro, Battaglia, Linati and Ghislandi, (2003) Farmaco    58:939-946; Cowan, (2003) International Journal of Clinical    Practice, Supplement 133:3-8; Hurley, Banfor and Hammond, (2003)    Neuroscience (Oxford, United Kingdom) 118:789-796; Neilan, King,    Rossi, Ansonoff, Pintar, Schiller and Pasternak, (2003) Brain    Research 974:254-257; Porreca and Hruby, (2003) Pain 407-419;    Servin, (2003) Advances in Experimental Medicine and Biology    523:245-260; Gilbert, Hosztafi, Mahurter and Pasternak, (2004)    European Journal of Pharmacology 492:123-130).    Inflammatory Pain-   (Gutstein and Akil, J. G. Hardman and L. E. Limbird (2001) The    pharmacological basis of therapeutics 569-619).    Immune Function-   (Renaud and Tomer, (1996) Advances in Experimental Medicine and    Biology 402:63-69; Sacerdote, Bianchi, Manfredi and Panerai, (1997)    Pain 72:325-330; Carrigan, Saurer, Ijames and Lysle, (2004)    International Immunopharmacology 4:419-428).    Visceral Pain-   (Kharkevich and Churukanov, (1999) European Journal of Pharmacology    375:121-131; Gebhart, (2000) Regional Anesthesia and Pain Medicine    25:632-638; Churukanov, (2003) Eksperimental'naya i Klinicheskaya    Farmakologiya 66:24-31).    Esophageal Reflux-   (Tonini, de Giorgio and de Ponti, (2004) Drugs 64:347-361).    Muscle Pain-   Nielsen, Mathiesen and Blackburn-Munro, (2004) European Journal of    Pharmacology 487:93-103).    Cancer Pain-   9Gutstein and Akil, J. G. Hardman and L. E. Limbird (2001) The    pharmacological basis of therapeutics 569-619; Wells, Bartlett,    Ananthan and Bilsky, (2001) Journal of Pharmacology and Experimental    Therapeutics 297:597-605; Valenzano, Miller, Chen, Shan, Crumley,    Victory, Davies, Huang, Allie, Nolan, Rotshteyn, Kyle and    Brogle, (2004) Journal of Pharmacology and Experimental Therapeutics    310:783-792).    Cough-   (Gutstein and Akil, J. G. Hardman and L. E. Limbird (2001) The    pharmacological basis of therapeutics 569-619).

Example 8 Delta, Mu Analgesic Synergy

Delta and mu opioid agonists have been repeatedly demonstrated toproduce antinociceptive synergy. (Vaught and Takemori, (1979) Journal ofPharmacology and Experimental Therapeutics 211:280-3; Vaught andTakemori, (1979) Journal of Pharmacology and Experimental Therapeutics208:86-90; Porreca, Jiang and Tallarida, (1990) European Journal ofPharmacology 179:463-8; Sufters, Miakowski, Taiwo and Levine, (1990)Brain Research 530:290-4; Horan, Tallarida, Haaseth, Matsunaga, Hrubyand Porreca, (1992) Life Sciences 50:1535-41; Malmberg and Yaksh, (1992)Journal of Pharmacology and Experimental Therapeutics 263:264-75; Adams,Tallarida, Geller and Adler, (1993) Journal of Pharmacology andExperimental Therapeutics 266:1261-7; Dykstra, Schoenbaum, Yarbrough,McNutt and Chang, (1993) Journal of Pharmacology and ExperimentalTherapeutics 267:875-82; Rossi, Pasternak and Bodnar, (1994) BrainResearch 665:85-93; Negri, Improta, Lattanzi, Potenza, Luchetti andMelchiorri, (1995) British Journal of Pharmacology 116:2931-8; Dykstra,Granger, Allen, Zhang and Rice, (2002) Psychopharmacology (Berlin,Germany) 163:420-429).

Example 9 Delta, Mu Reduced Side Effect Profile

Combinations of delta and mu opioid agonists have demonstrated reducedside effect profiles including fewer convulsions, lower incidence ofstraub tail, and attenuated respiratory depression (O'Neill, Collins,Pettit, McNutt and Chang, (1997) Journal of Pharmacology andExperimental Therapeutics 282:271-277; Su, McNutt and Chang, (1998)Journal of Pharmacology and Experimental Therapeutics 287:815-823).Therefore compounds dually embodying delta and mu opioid pharmacologieswill have greater analgesic action and a reduced side effect profilethan that derived from either sole pharmacology.

1. A compound of Formula 1

wherein: R₁ is hydroxy, aminocarbonyl, hydroxyamidino, formylamino;C₁₋₄alkanylaminocarbonyl; phenyl-aminocarbonyl;phenyl(C₁₋₄)alkanylaminocarbonyl; and naphthyl- and phenyl- aminowherein the naphthyl and phenyl are optionally substituted with one totwo substitutents independently selected from the group consisting ofC₁₋₄alkanyl, C₁₋₄alkoxy, halogen, and hydroxy; or pyridinylamino; R₂ isselected from the group consisting of hydrogen, C₁₋₄alkanyl,C₂₋₈alkenyl, C₂₋₈alkynyl, C₃₋₈cycloalkanyl(C₁₋₄)alkanyl,C₁₋₄alkanyloxy(C₁₋₄)alkanyl, C₁₋₄alkanylthio(C ₁₋₄)alkanyl,hydroxyC₁₋₄alkanyl, thioformyl, phenylimino(C₁₋₄)alkanyl,phenyl(C₁₋₄)alkanyl, and heteroaryl(C₁₋₄)alkanyl wherein heteroaryl isselected from the group consisting of benzo [1,3 ]dioxolyl, imidazolyl,furanyl, pyridinyl, thienyl, indolyl, indolinyl, isoquinolinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,benzothiophenyl, tetrazolyl; wherein phenyl and heteroaryl areoptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₆alkanyloxy and hydroxy; oroptionally, when phenyl and heteroaryl are optionally substituted withtwo substituents attached to adjacent carbon atoms, the two substituentstogether form —O(CH₂)₁₋₃O—; A is —(CH₂)₂—; Y is O; and enantiomers,diastereomers, tautomers, or pharmaceutically acceptable salts thereof.2. The compound of claim 1 wherein: R₁ is hydroxy, aminocarbonyl,formylamino; phenyl-aminocarbonyl; or pyridinylamino; R₂ is selectedfrom the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl,3-methyl-but-2-enyl, propynyl, hydroxyethyl, C₃₋₅ cycloalkanylmethyl,methylthioethyl, methoxyethyl, thioformyl, phenyliminomethyl, phenethyl,and heteroaryl(C₁₋₂)alkanyl wherein the heteroaryl is selected from thegroup consisting of benzo[1,3] dioxolyl, imidazolyl, furanyl, pyridinyl,thienyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl,benzothiophenyl, tetrazolyl; wherein the phenyl in any phenyl-containingsubstituent and the pyridinyl substituent are optionally substitutedwith one hydroxyl group; and enantiomers, diastereomers, tautomers, orpharmaceutically acceptable salts thereof.
 3. The compound of claim 1wherein: R₁ is hydroxy, aminocarbonyl, formylamino;phenyl-aminocarbonyl; or phenyl(C ₁₋₄)alkanylaminocarbonyl; R₂ ishydrogen, methyl, allyl, 3-methyl-but-2-enyl, cyclopropylmethyl,phenylmethyl, or heteroarylmethyl wherein heteroaryl is selected fromthe group consisting of benzo [1,3] dioxolyl, imidazolyl, furanyl,pyridinyl, and thienyl; and enantiomers, diastereomers, tautomers, orpharmaceutically acceptable salts thereof.
 4. The compound of claim 3wherein: R₁ is hydroxy, aminocarbonyl, formylamino;phenyl-aminocarbonyl; or phenylmethylaminocarbonyl; R₂ is hydrogen,methyl, 3-methyl-but-2-enyl, cyclopropylmethyl, phenylmethyl,pyridin-2-ylmethyl, pyridin-3 -ylmethyl, pyridin-4-ylmethyl,2-hydroxy-pyridine-4-ylmethyl, imidazol-2-ylmethyl, thien-2-ylmethyl, orfuran-3 -ylmethyl; and enantiomers, diastereomers, tautomers, orpharmaceutically acceptable salts thereof.
 5. A compound of Formula (Ia)

selected from the group consisting of a compound of Formula (Ia) whereinR₁ is methoxy, A is —(CH₂)₂—, and R₂ is H; a compound of Formula (Ia)wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ is H; a compound of Formula(Ia) wherein R₁ is aminocarbonyl, A is —(CH₂)₂—, and R₂ is H; a compoundof Formula (Ia) wherein R₁ is aminocarbonyl, A is —(CH₂)₂—, and R₂ isfuran-2-ylmethyl; Enant. A, a compound of Formula (Ia) wherein R₁ ishydroxy, A is —(CH₂)₂—, and R₂ is trifluoromethylcarbonyl; Enant. B, acompound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ istrifluoromethylcarbonyl; a compound of Formula (Ia) wherein R₁ ishydroxy, A is —(CH₂)₂—, and R₂ is H; a compound of Formula (Ia) whereinR₁ is hydroxy, A is —(CH₂)₂—, and R₂ is H; a compound of Formula (Ia)wherein R₁ is methylaminocarbonyl, A is —(CH₂)₂—, and R₂is H; a compoundof Formula (Ia) wherein R₁ is dimethylaminocarbonyl, A is —(CH₂)₂—, andR₂is H; a compound of Formula (Ia) wherein R₁ is phenyl-aminocarbonyl, Ais —(CH₂)₂-, and R₂is H; a compound of Formula (Ia) wherein R₁ isphenylmethyl-aminocarbonyl, A is —(CH₂)₂-, and R₂ is H; a compound ofFormula (Ia) wherein R₁ is phenylethyl-aminocarbonyl, A is —(CH₂)₂-, andR₂ is H; a compound of Formula (Ia) wherein R₁ is(2-dimethylamino-ethyl) aminocarbonyl, A is —(CH₂)₂—, and R₂ is H; acompound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ ismethyl; a compound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—,and R₂ is pyridin-2-ylmethyl; a compound of Formula (Ia) wherein R₁ ishydroxy, A is —(CH₂)₂—, and R₂ is pyridin-4-ylmethyl; a compound ofFormula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ is2-hydroxy-pyridin-4-ylmethyl; a compound of Formula (Ia) wherein R₁ ishydroxy, A is —(CH₂)₂—, and R₂ is thien-2-ylmethyl; a compound ofFormula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ is furan-3-ylmethyl; a compound of Formula (Ia) wherein R₁ is hydroxy, A is—(CH₂)₂—, and R₂ is cyclopropylmethyl; a compound of Formula (Ia)wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ is 2-methyl-but-2-enyl; acompound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ is2-phenyl-imidazol-4-ylmethyl; a compound of Formula (Ia) wherein R₁ isaminocarbonyl, A is —(CH₂)₂—, and R₂ is trifluoromethylcarbonyl acompound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ isphenethyl; a compound of Formula (Ia) wherein R₁ is hydroxy, A is—(CH₂)₂—, and R₂ is pyridin-2-ylmethyl; a compound of Formula (Ia)wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ is phenylmethyl; a compoundof Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ isbenzothien-3 -ylmethyl; a compound of Formula (Ia) wherein R₁ ishydroxy, A is —(CH₂)₂—, and R₂ is 1H-imidazol-2-ylmethyl; a compound ofFormula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ isisoquinolin-5 -ylmethyl; Enant. A, a compound of Formula (Ia) wherein R₁is aminocarbonyl, A is —(CH₂)₂—, and R₂ is trifluoromethylcarbonyl;Enant. A, a compound of Formula (Ia) wherein R₁ is aminocarbonyl, A is—(CH₂)₂—, and R₂is H; Enant. B, a compound of Formula (Ia) wherein R₁ isaminocarbonyl, A is —(CH₂)₂—, and R₂ is trifluoromethtylcarbonyl; Enant.A, a compound of Formula (Ia) wherein R₁ is aminocarbonyl, A is—(CH₂)₂—, and R₂is H; a compound of Formula (Ia) wherein R₁ is amino, Ais —(CH₂)₂—, and R₂ is H; Enant. A, a compound of Formula (Ia) whereinR₁ is hydroxyamidino, A is —(CH₂)₂—, and R₂ is H; a compound of Formula(Ia) wherein R₁ is formylamino, A is —(CH₂)₂—, and R₂ is H; Enant. A, acompound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ isphenylmethyl; Enant. B, a compound of Formula (Ia) wherein R₁ ishydroxy, A is —(CH₂)₂—, and R₂ is phenylmethyl; a compound of Formula(Ia) wherein R₁ is phenylaminocarbonyl, A is —(CH₂)₂—, and R₂ is H; acompound of Formula (Ia) wherein R₁ is phenylaminocarbonyl, A is—(CH₂)₂—, and R₂ is H; Enant. A, a compound of Formula (Ia) wherein R₁is hydroxy, A is —(CH₂)₂—, and R₂ is pyridin-3-ylmethyl; Enant. B, acompound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ ispyridin-3-ylmethyl; Enant. A, a compound of Formula (Ia) wherein R₁ ishydroxy, A is —(CH₂)₂—, and R₂ is methyl; Enant. B, a compound ofFormula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ is methyl;Enant. A, a compound of Formula (Ia) wherein R₁ isphenylmethylaminocarbonyl, A is —(CH₂)₂—, and R₂ is H; Enant. B, acompound of Formula (Ia) wherein R₁ is phenylmethylaminocarbonyl, A is—(CH₂)₂—, and R₂ is H; Enant. A, a compound of Formula (Ia) wherein R₁is phenethylaminocarbonyl, A is —(CH₂)₂—, and R₂ is H; Enant. B, acompound of Formula (Ia) wherein R₁ is phenethylaminocarbonyl, A is—(CH₂)₂—, and R₂ is H; Enant. B, a compound of Formula (Ia) wherein R₁is hydroxy, A is —(CH₂)₂—, and R₂ is furan-3-ylmethyl; Enant. A, acompound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ isfuran-3-ylmethyl; Enant. A, a compound of Formula (Ia) wherein R₁ ishydroxy, A is —(CH₂)₂—, and R₂ is pyridin-2-ylmethyl; Enant. B, acompound of Formula (Ia) wherein R₁ is hydroxy, A is —(CH₂)₂—, and R₂ ispyridin-2-ylmethyl; a compound of Formula (Ia) wherein R₁ is4-chioro-phenylamino, A is —(CH₂)₂—, and R₂is H; a compound of Formula(Ia) wherein R₁ is pyridin-3-ylamino, A is —(CH₂)₂—, and R₂ is H; and acompound of Formula (Ia) wherein R₁ is phenylamino, A is —(CH₂)₂—, andR₂ is H.
 6. A composition comprising the (+) enantiomer of a compound ofclaim 1 wherein said composition is substantially free from the (−)isomer of said compound.
 7. A composition comprising the (−) enantiomerof a compound of claim 1 wherein said composition is substantially freefrom the (+) isomer of said compound.
 8. A pharmaceutical compositioncomprising a compound or salt according to claim 1 admixed with apharmaceutically acceptable carrier, excipient or diluent.
 9. Aveterinary composition comprising a compound or salt according to claim1 admixed with a veterinarily acceptable carrier, excipient or diluent.10. A pharmaceutical composition comprising a compound or salt accordingto claim 1 admixed with a pharmaceutically acceptable carrier, excipientor diluent.
 11. A veterinary composition comprising a compound or saltaccording to claim 1 admixed with a veterinarily acceptable carrier,excipient or diluent.
 12. A pharmaceutical composition comprising acompound or salt according to claim 2 admixed with a pharmaceuticallyacceptable carrier, excipient or diluent.
 13. A veterinary compositioncomprising a compound or salt according to claim 2 admixed with aveterinarily acceptable carrier, excipient or diluent.
 14. Apharmaceutical composition comprising a compound or salt according toclaim 3 admixed with a pharmaceutically acceptable carrier, excipient ordiluent.
 15. A veterinary composition comprising a compound or saltaccording to claim 3 admixed with a veterinarily acceptable carrier,excipient or diluent.
 16. A pharmaceutical composition comprising acompound or salt according to claim 4 admixed with a pharmaceuticallyacceptable carrier, excipient or diluent.
 17. A veterinary compositioncomprising a compound or salt according to claim 4 admixed with aveterinarily acceptable carrier, excipient or diluent.